Organocatalytic intramolecular aza-Michael reaction

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of organocatalytic enantioselective intramolecular aza-Michael reactions. (IMAMR) for α .... la data es basen en la utilització d'organocatalitzadors. La principal ...
Organocatalytic intramolecular aza-Michael reaction with enones and acid derivatives: New strategies

Cristina Mulet Chorro H14

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València 2016

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FACULTAD DE FARMACIA Departamento de Química Orgánica Programa de Doctorado en Química (3056) con Mención de Excelencia

Reacción aza-Michael intramolecular organocatalítica sobre enonas y derivados de ácido: Nuevas estrategias Tesis Doctoral Cristina Mulet Chorro

Dirigida por: Prof. Santos Fustero Lardiés Dr. Carlos del Pozo Losada

Valencia Septiembre 2016

Prof. Santos Fustero Lardiés, Catedrático de Química Orgánica del Departamento de Química Orgánica de la Universidad de Valencia Dr. Carlos del Pozo Losada, Profesor titular de Química Orgánica del Departamento de Química Orgánica de la Universidad de Valencia

CERTIFICAN:

Que la presente Tesis Doctoral, titulada “Reacción azaMichael intramolecular organocatalítica sobre enonas y derivados de ácido: Nuevas estrategias” ha sido realizada bajo su dirección en el Departamento de Química Orgánica de la Universidad deValencia, por la licenciada en Farmacia Dña. Cristina Mulet Chorro y autorizan su presentación para que sea calificada como Tesis Doctoral.

Valencia, Septiembre 2016

Fdo. Santos Fustero Lardiés

Fdo. Carlos del Pozo Losada

Fdo. Cristina Mulet Chorro

I

II

ABBREVIATIONS

List of Abbreviations

IV

List of Abbreviations

List of Abbreviations Å aa Ac Ar BEMP

Bn Boc br BTFMBA Bu Calcd. Cbz CM conv. CPME CSA Cy d DBU DCE DCM Decomp. DIC DMAP DMF DMP DNBSA DPP d.r. E

Angstroms Amino acid Acetyl Aryl 2-Tert-Butylimino-2diethylamino-1,3dimethylperhydro-1,3,2diazaphosphorine Benzyl Tert-butyloxycarbonyl Broad 3,5-Bis(trifluoromethyl)benzoic acid Butyl Calculated Benzyloxycarbonyl Cross metathesis Conversion Cyclopentyl methyl ether (+)-10-Camphorsulfonic acid Cyclohexyl Doblet 1,8-Diazabicycloundec7-ene Dichloroethane Dichloromethane Decomposition Diisopropyl carbodiimide 4-Dimethylaminopyridine N,N-Dimethylformamide 3,5-Dimethyl pyrazole 2,4-Dinitro-benzene sulfonic acid Diphenylphospinoyl Diastereomeric relation Electrophile

ee EI equiv. er Et EWG FAB FDA G-I G-II h HG-II

HOMO HPLC HRMS Hz IMAMR iPr IR KHMDS LA LDA LG LiHMDS lit. LUMO

Enantiomeric excess Electronic impact Equivalent/s Enantiomeric relation Ethyl Electro withdrawing group Fast atom bombardment Food and Drug Administration Grubbs first-generation catalyst Grubbs secondgeneration catalyst hours Hoveyda-Grubbs second-generation catalyst Highest occupied molecular orbital High-performance liquid chromatography High resolution mass Spectrometry Hertzs Intramolecular azaMichael reaction Isopropyl Infrared Potassium hexamethyldisilazide Lewis acid Lithium diisopropylamide Leaving group Lithium hexamethyldisilazide Literature Lowest unoccupied V

List of Abbreviations

molecular orbital m Multiplet M Molar mayor Majoritary MBH Morita-Baylis-Hillman Me Methyl Mes Mesityl (2,4,6trimethyl phenyl) min Minutes minor Minority mmol Milimols m.p. Melting point Ms Methanesulfonyl (mesyl) MS Molecular sieves MTBE Methyl tert-butyl ether MW Microwave NaHMDS Sodium hexamethyldisilazide N-Cbz-LP N-Benzyloxycarbonyl-Lphenylalanine NMR Nuclear magnetic resonance Ns Nitrobenzenesulfonyl (nosyl) Nu Nucleophile oOrto OC Organocatalyst pPara PC Peptide coupling PFPA Pentafluoropropionic acid Ph Phenyl Pent Pentyl

VI

PG PMP p-NBA ppm Pr prod. py q RID r.t. s SM t t T TBAF TBDMS TCE TES Tf TFA THF TLC TMS Tol Ts TSA UV UVD d

Protecting group p-Methoxyphenyl p-Nitrobenzoic acid Part-per-million Propyl Product Pyridine Quadruplet Refractive index detector Room temperature singlet Starting material Triplet Time Temperature Tetrabutylammonium fluoride tert-Butyldimethylsilyl 1,1,2-Trichloroethane Triethylsilyl ether Triflate Trifluoroacetic acid Tetrahydrofuran Thin layer chromatography Trimethylsilyl Toluene p-Toluenesulfonyl (tosyl) Toluene sulfonic acid Ultraviolet Ultraviolet detector Chemical shift

ABSTRACT RESUMEN RESUM

Abstract/Resumen/Resum

Abstract For the creation of carbon-nitrogen bonds and to access b-amino carbonylic compounds, together with the Mannich reaction, the aza-Michael reaction is considered one of the more appealing methodologies. It consists on the conjugate addition of a nucleophilic nitrogen source to an a,b-unsaturated system. This reaction has acquired a special relevance in its intramolecular version as it conducts to the formation of nitrogen heterocycles in a very straightforward manner. Furthermore, when the activated olefin contains prochiral centers, there are generated one or more stereogenic centers through the addition process. Thus, the asymmetric version of this transformation would allow the preparation of stereoselective functionalized nitrogen-containing compounds. Whereas the conjugate addition of chiral amines to electronic deficient olefins has been the most employed strategy among the asymmetric azaMichael reactions, the emergence of catalytic variants came late. Likewise, the asymmetric version of the intramolecular aza-Michael reaction has practically remained unexplored, being just organocatalyzed processes the few described examples. The main constraint of the organocatalytic enantioselective aza-Micheal reaction is that the Michael acceptors are generally a,b-unsaturated aldehydes. The greater difficulty that implies the generation of the corresponding iminium ion with ketones has made the catalysis with these substrates a more compromised task. In this way, the use of primary amines, where the kinetic for the formation of the iminium intermediate is more favorable, has enabled a more efficient use of this transformation in its intermolecular version. Similarly, the employment of a,b-unsaturated esters as Michael acceptors is not very extended and even less within the organocatalysis field. In this cases the activation process will always be through hydrogen bondings, since the ester group is not enough reactive as to form the iminium salt observed with aldehydes and ketones. Due to this poor reactivity of the conjugated esters, there have been developed a great variety of synthetic equivalents that either show an enhanced reactivity as electrophiles or they

IX

Abstract/Resumen/Resum

facilitate the activation process and the formation of a more stable transition state through their hydrogen-bonding acceptors. Taking the aforementioned into account and given the relevance of the asymmetric synthesis in organic chemistry, the objectives of the present PhD Thesis are focused on one hand, in the design of more general methodologies of organocatalytic enantioselective intramolecular aza-Michael reactions (IMAMR) for a,b-unsaturated ketones and esters; and on the other hand, in the application of those methodologies to the synthesis of structures of high interest, such as sultams. The starting materials required to study the IMAMR are prepared through a cross-metathesis (CM) reaction between the a,b-unsaturated carbonylic compounds and the corresponding properly protected amines. The latter will be in turn obtained following procedures similar to those described in the literature. Once with the IMAMR substrates in hand, there will be studied the reaction conditions (solvent, temperature, catalyst, additive, …) to execute the intramolecular addition in an enantioselective fashion. In conclusion, there have been developed several highly enantioselective protocols for the preparation of nitrogen heterocycles containing b-amino carbonylic motifs, applying chiral organocatalysts to activate a,b-unsaturated ketones and ester surrogates in the intramolecular aza-Michael reaction. Moreover, it has been achieved the application of one of these methodologies for the preparation of bicyclic sultams with a structural composition not described to date.

X

Abstract/Resumen/Resum

Resumen Una de las metodologías más importantes, junto con la reacción de Mannich, para formar enlaces carbono-nitrógeno y acceder a compuestos bamino carbonílicos, es la reacción aza-Michael, que consiste en la adición conjugada de una fuente de nitrógeno nucleófila a un sistema a,b-insaturado. Esta reacción adquiere una especial relevancia en su versión intramolecular ya que conduce a la formación de heterociclos nitrogenados de forma sencilla. Además, cuando la olefina activada contiene centros proquirales, en el proceso de adición se generan uno o más centros estereogénicos, por lo que la versión asimétrica de esta reacción permitiría obtener compuestos nitrogenados funcionalizados de forma estereoselectiva. Mientras que la adición conjugada de aminas quirales a olefinas electrónicamente deficientes ha sido la estrategia más utilizada en la reacción aza-Michael asimétrica, la aparición de las variantes catalíticas ha sido mucho más tardía. De la misma forma, la versión asimétrica de la reacción azaMichael intramolecular ha permanecido prácticamente inexplorada, y los ejemplos

descritos

hasta

la

fecha

se

basan

en

el

empleo

de

organocatalizadores. La

principal

limitación

que

presenta

la

reacción

aza-Michael

organocatalítica enantioselectiva es que habitualmente los aceptores de Michael son aldehídos a,b-insaturados. La mayor dificultad que supone generar la correspondiente sal de iminio con cetonas ha hecho que la catálisis con estos sustratos sea más comprometida. En este sentido, el empleo de aminas primarias, donde la formación de la sal de iminio tiene una cinética más favorable, ha permitido efectuar esta transformación de forma eficaz en su versión intermolecular. Asimismo, la utilización de ésteres a,b-insaturados como aceptores de Michael no está muy extendida y aún menos en el campo de la organocatálisis. En estos casos la activación será siempre por enlaces de hidrógeno, puesto que el grupo éster es muy poco reactivo como para dar lugar a la formación del ion iminio observado con aldehídos y cetonas. Debido a esta baja reactividad de los ésteres conjugados, se han descrito muchos equivalentes sintéticos que

XI

Abstract/Resumen/Resum

o bien presentan una mayor reactividad como electrófilos o bien permiten una mayor activación y fijación del estado de transición por presentar más puntos de anclaje de enlaces de hidrógeno. Teniendo en cuenta lo expuesto anteriormente y dada la importancia de la síntesis asimétrica en química orgánica, los objetivos de la presente Tesis Doctoral se centran, por un lado, en el diseño de metodologías más generales de reacciones aza-Michael intramoleculares (AMIM) enantioselectivas y organocatalíticas para cetonas y ésteres a,b-insaturados; y por otra parte, en la aplicación de dichas metodologías a la síntesis de estructuras de elevado interés biológico, como por ejemplo las sultamas. Los compuestos de partida para llevar a cabo las reacciones AMIM se prepararán a través de una reacción de metátesis cruzada (CM, crossmetathesis)

entre

los

compuestos

carbonílicos

a,b-insaturados

y

las

correspondientes aminas adecuadamente protegidas. Éstas últimas se obtendrán a su vez siguiendo procedimientos similares a los descritos en la bibliografía. Una vez preparados los sustratos para la reacción aza-Michael, se estudiarán las condiciones de reacción (disolvente, temperatura, catalizador, aditivo, …) que permitan efectuar esta adición intramolecular de forma enantioselectiva. En conclusión, se han desarrollado diversos protocolos altamente enantioselectivos para la preparación de heterociclos nitrogenados con unidades b-amino carbonílicas empleando organocatalizadores quirales para la activación

de

la

reacción

aza-Michael

intramolecular

con

cetonas

y

equivalentes de ésteres a,b-insaturados. Además, se ha conseguido aplicar una de estas metodologías para la preparación de sultamas bicíclicas con una distribución estructural no descrita hasta el momento.

XII

Abstract/Resumen/Resum

Resum Una de les metodologies més importants, junt amb la reacció de Mannich, per la formació d’enllaços carboni-nitrogen i per accedir a compostos b-amino carbonílics, és la reacció aza-Michael, que consisteix en l’addició conjugada d’una font de nitrogen nucleòfila a un sistema a,b-insaturat. Aquesta reacció adquireix una especial rellevància a la seua versió intramolecular ja que condueix a la formació d’heterocicles nitrogenats de forma senzilla. A més, quan l’olefina activada conté centres proquirals, al procés d’addició es generen un o més centres estereogènics, pel que la versió asimètrica d’esta reacció permetria

obtenir

compostos

nitrogenats

funcionalitats

de

forma

estereoselectiva. Mentre

que

l’addició

conjugada

de

amines

quirals

a

olefines

electrònicament deficients ha sigut l’estratègia més utilitzada a la reacció azaMichael asimètrica, l’aparició de les variants catalítiques ha sigut molt més tardana. De la mateixa manera, la versió asimètrica de la reacció aza-Michael intramolecular ha romàs pràcticament inexplorada, i els exemples descrits fins la data es basen en la utilització d’organocatalitzadors. La

principal

limitació

que

presenta

la

reacció

aza-Michael

organocatalítica enantioselectiva és que habitualment els acceptors de Michael són aldehids a,b-insaturats. La major dificultat que suposa generar la corresponent sal d’imini amb cetones ha fet que la catàlisi amb aquests substrats estiga més compromesa. En aquest sentit, la utilització de amines primàries, on la formació de la sal d’imini té una cinètica més favorable, ha permès efectuar aquesta transformació de forma eficaç en la seua versió intermolecular. Així mateix, la utilització d’èsters a,b-insaturats com acceptors de Michael no està molt estesa i encara menys al camp de l’organocatàlisi. En aquests casos l’activació serà sempre per enllaços d’hidrogen, posat que el grup èster és molt poc reactiu com per donar lloc a la formació de l’ió imini observat amb aldehids i cetones. Degut a aquesta baixa reactivitat dels èsters conjugats, s’han descrit molts equivalents sintètics que o bé presenten una

XIII

Abstract/Resumen/Resum

major reactivitat com a electròfils o bé permeten una major activació i fixació de l’estat de transició al presentar més punts d’ancoratge d’enllaços d’hidrogen. Tenint en compte l’exposat anteriorment i donada la importància de la síntesi asimètrica en química orgànica, els objectius de la present Tesi Doctoral es centren, por una banda, en el disseny de metodologies més generales de reaccions

aza-Michael

intramoleculars

(AMIM)

enantioselectives

i

organocatalítiques per cetones y èsters a,b-insaturats; i por altra banda, en l’aplicació de dites metodologies a la síntesi d’estructures d’elevat interès biològic, com per exemple les sultames. Els substrats de partida per realitzar les reaccions AMIM es prepararan a través d’una reacció de metàtesi creuada (CM, cross-metathesis) entre els compostos

carbonílics

a,b-insaturats

i

les

corresponents

amines

adequadament protegides. Aquestes últimes s’obtindran a la seua vegada seguint procediments similars als descrits a la bibliografia. Una vegada preparats els substrats per la reacció aza-Michael, s’estudiaran les condicions de reacció (dissolvent, temperatura, catalitzador, additiu, …) què permeten efectuar aquesta addició intramolecular de forma enantioselectiva. En

conclusió,

s’han

desenvolupat

diversos

protocols

altament

enantioselectius per la preparació d’heterocicles nitrogenats amb unitats bamino carboníliques utilitzant organocatalitzadors quirals per l’activació de la reacció aza-Michael intramolecular amb cetones i equivalents d’èsters a,binsaturats. A més, s’ha aconseguit aplicar una d’aquestes metodologies per la preparació de sultames bicícliques amb una distribució estructural no descrita fins el moment.

XIV

INDEX

Index

Index 0. General introduction and objectives ............................................ 1 0.1. General Introduction ............................................................. 3 0.1.1. Asymmetric synthesis .................................................................. 3 0.1.2. Organocatalysis ......................................................................... 7 0.1.3. b-Amino carbonyl compounds: aza-Michael reaction ............................ 25

0.2. General Objectives .............................................................. 29 1. Organocatalytic enantioselective intramolecular aza-Michael reaction with conjugated ketones. ......................................................... 31 1.1. Background ........................................................................ 33 1.1.1. Aza-Michael reaction ................................................................. 33 1.1.2. Enantioselective synthesis of benzofused heterocylcic systems ............... 45

1.2. Objectives ......................................................................... 57 1.3. Results and Discussion ........................................................... 59 1.3.1. Preparation of the starting materials .............................................. 59 1.3.1.1. Synthesis of the N-protected amino-olefins 1 and 2 ................................. 60 1.3.1.2. Synthesis of the N-Cbz protected o-allyl anilines 3 .................................. 60 1.3.1.3. Synthesis of the N-Cbz protected o-vinyl benzyl amine 4 ........................... 61 1.3.1.4. Synthesis of the N-Cbz protected o-homoallyl anilines 5............................ 62 1.3.1.5. Synthesis of the N-Cbz protected o-allyl benzyl amine 6 ........................... 62 1.3.1.6. Synthesis of the N-Cbz protected o-vinyl phenethyl amine 7....................... 63

1.3.2. Cross-Metathesis reaction............................................................ 63 1.3.3. Optimisation of the intramolecular aza-Michael reaction conditions ......... 67 1.3.4. Enantioselective synthesis of monocyclic N-heterocycles: piperidines 35 and pyrrolidine 36 .......................................................................... 72 1.3.5. Enantioselective synthesis of benzofused N-heterocycles: indolines 37, isoindolines 38, tetrahydroquinolines 39 and tetrahydroisoquinolines 4041….. .................................................................................... 74 1.3.6. Mechanistic proposal for the intramolecular aza-Michael reaction between carbamates and a,b-unsaturated ketones ........................................ 77

1.4. Recent contributions to the IMAMR with enones ............................ 78 1.1. Conclusions ........................................................................ 83 1.2. Experimental Section ............................................................ 85 1.2.1. General methods ...................................................................... 85 1.2.1.1. Spectroscopical and physical technics ................................................. 85

Index 1.2.1.2. Cromatographic technics ................................................................. 86 1.2.1.3. Solvents drying ............................................................................. 86 1.2.1.4. Reagents and reaction conditions ....................................................... 87

1.2.2. Synthesis of the N-protected a,b-unsaturated ketoamines 27-33 ............. 87 1.2.3. Michael adducts synthesis: Preparation of 2-Substituted Nitrogen heterocycles 35-41 .................................................................... 94 1.2.4. HPLC traces of enantioenriched compounds 35-41 ............................ 104

2. Organocatalytic enantioselective intramolecular aza-Michael reaction with conjugated ester surrogates ............................................. 127 2.1. Background .......................................................................129 2.1.1. Organocatalytic activation of esters and ester surrogates ................... 129 2.1.2. Aza-Michael reactions with ester derivatives as Michael acceptors ......... 135 2.1.3. Organocatalytic intramolecular aza-michael reactions in domino processes….. ......................................................................... 138 2.1.4. Conjugated ester surrogates as acceptors in Michael-type reactions ....... 145

2.2. Objectives ........................................................................149 2.3. Results and discussion ..........................................................151 2.3.1. Search of suitable starting materials ............................................ 151 2.3.1.1. Study of alkyl amine conjugated esters 42 and 43 .................................. 151 2.3.1.2. Study of sulfonamide conjugated esters 55 and 56 ................................. 156 2.3.1.3. Study of N-Cbz-protected amine conjugated ester and surrogates 65-68 ....... 158 2.3.1.4. Study of sulfonamide conjugated ester surrogates 78-82 .......................... 160

2.3.2. Enantioselective synthesis of piperidines, pyrrolidines, isoindoline and tetrahydroisoquinolines 84 and 93-96 ............................................ 168 2.3.3. Enantioselective synthesis of 6-membered ring N-heterocycles through a domino process ...................................................................... 171 2.3.4. Transformation of surrogates into the corresponding enantioenriched esters.................................................................................. 175 2.3.5. Mechanistic proposal for the intramolecular aza-Michael reaction between sulfonamides and a,b-unsaturated N-acyl pyrazoles ......................... 176

2.4. Conclusions .......................................................................179 2.5. Experimental Section ...........................................................181 2.5.1. Preparation of the terminal-olefin N-protected amines ...................... 181 2.5.1.1. General procedure for the preparation of N-protected amines, including 99, 100.. ........................................................................................ 181

Index 2.5.1.2. Synthesis of diethyl 2-allyl-2-{2-[(4-methylphenyl)sulfonamido] ethyl}malonate 124 .......................................................................................... 183 2.5.1.3. Synthesis of N-Allyl-N-benzyl-2-[(4-methylphenyl)sulfonamido] acetamide 129……. ..................................................................................... 184

2.5.2. Preparation of the a,b-unsaturated N-protected amines candidates for IMAMR substrates .................................................................... 185 2.5.3. Michael adducts synthesis: Preparation of 2-substituted nitrogen heterocycles 84a-e and 93-96 ..................................................... 194 2.5.4. Michael adducts synthesis: Preparation of sulfonamido esters and sulfonamido acids ................................................................... 202 2.5.5. General procedure for the domino PC-IMAMR: preparation of 2-substituted nitrogen heterocycles 84c,f-i and 93b. .......................................... 208 2.5.6. General procedure for the transformation of pyrazolamides 84 and 93 into esters 136 and 137 .................................................................. 213 2.5.7. HPLC traces and NMR er determination spectra of enantioenriched compounds 84 and 93-96 ........................................................... 215

3. Organocatalytic synthesis of enantioenriched bicyclic sultams ......... 231 3.1. Background .......................................................................233 3.1.1. Michael additions to vinyl sulfones ............................................... 233 3.1.2. Sultams ............................................................................... 239

3.2. Objectives ........................................................................243 3.3. Results and Discussion ..........................................................245 3.3.1. Preparation of the starting materials ............................................ 245 3.3.2. Enantioselective intramolecular aza-Michael reaction of a,b-unsaturated sulfonamide-ketones 140 .......................................................... 249 3.3.3. Diastereoselective intramolecular Michael reaction of N-heterocyclic a,bunsaturated sulfonamides 141 .................................................... 252 3.3.4. Complementary ongoing work..................................................... 256

3.4. Conclusions .......................................................................259 3.5. Experimental Section ...........................................................261 3.5.1. Preparation of functionalised sulfonamides 142 ............................... 261 3.5.2. Synthesis of N-conjugated sulfonamide a,b-unsaturated ketoamines 140 . 262 3.5.3. Aza-Michael adduct synthesis: Preparation of 2-substituted nitrogen heterocycles 141 .................................................................... 265 3.5.4. Michael adduct synthesis: Preparation of sultams 142 ........................ 268 3.5.5. HPLC traces of enantioenriched compounds 141 and 142 .................... 272

GENERAL INTRODUCTION AND OBJECTIVES 0.

General introduction and objectives

General Introduction

0.1. General Introduction 0.1.1. ASYMMETRIC SYNTHESIS Among the diverse areas of influence of organic chemistry research, design and synthesis of new drugs occupy a prominent place, and amazing amount of resources are devoted to this endeavour due to the relevance of this task. The main goal of drug design is to prepare defined molecular structures with an expected therapeutic action. Therefore, the study of new synthetic methods that gains access to those tailor-made compounds can have a significant impact in the drug discovery process. At the same time, the need of more green and environmentally friendly processes drives current research efforts for the preparation of both new and existing drugs. Asymmetric synthesis plays a key role in drug development, since one half of the currently marketed drugs contain at least one stereocenter, and among the top ten best selling drugs nine are composed of chiral molecules. The importance of the concept of chirality in Nature and in research it is known since long time ago, and the first to coin the term chiral (from Greek kheir: hand) was Lord Kelvin by the end of the nineteenth century.1 Besides, the significance of stereoisomerism in relation to biological activity has been recognized by scientists since 1848, when Louis Pasteur discovered the optical isomerism of tartaric acid. Nevertheless, the tools for either the resolution of racemates or for the synthesis of enantiomerically pure drugs were discovered and developed slowly. The pharmaceutical companies were already marketing demanded drugs in racemic form,2 not being noticed the relevance of the exploration of the in vivo differences between enantiomers, or other chemically equivalent forms, until the early 1960’s with the tragedy of thalidomide.3 Then, in 1987, the FDA issued a set of guidelines on the submission of New Drug Applications, where the question of stereochemistry was approached directly in the guideline on the

1

Cintas, P. Angew. Chem. Int. Ed. 2007, 46, 4016–4024. Camp, W. H. D. E. Chirality 1989, 1, 2–6. 3 Rubey, W. W.; Morse, P. M.; Tatum, E. L. Science. 1962, 137, 497–497. 2

3

General Introduction

manufacturing of drug substances. 4 Such marketing regulations for synthetic drugs, coupled with recent progress in stereoselective organic synthesis, resulted in a significant increase in the proportion of single-enantiomer drugs. In the case of thalidomide (Figure 0.1.a), the racemate (mixture of the (+)-(R)- and (-)-(S)-enantiomers) was introduced as a sleep-inducing agent in 1956, but it was withdrawn in 1961 for causing fetal malformations, that were lately related just to the levogyre enantiomer.5 This is the most famous one, but not the only case of undesirable side effects caused by the different behaviour of each enantiomer of a given drug in the human body.6 In 1982 was taken off the market a racemic preparation of benoxaprofen (Figure 0.1.b), Oraflex, once British physicians had written about its problems and after 26 patients who had taken it died of liver or kidney disorders.7 Benoxaprofen is an anti-inflammatory compound that was at an advanced stage of clinical evaluation, when it was found that the (-)-(R)-enantiomer was inverted to the (+)-(S)-form in vivo, which was traduced in the accumulation of the eutomer8 and the appearance of the overdose symptoms.9 O

O

N

O NH

O

O

Cl N

OH Me

O

(-)-(S)-thalidomide

(+)-(S)-benoxaprofen

(a)

(b)

Figure 0.1. Drugs with different behaviour in each enantiomer.

Until the early seventies the scientific knowledge about asymmetric synthesis and asymmetric induction wasn’t very wide. Then in 1983 it was finally published a five-volume treatise 10 that included the last 10 years advances in the field of asymmetric synthesis. From this starting point, the 4

Office of Drug Evaluation and Research (HFD-loo), F. and D. A. Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances; 5600 Fishers Lane, Rockville, MD 20857, 1987; pp 3–4. 5 Eriksson, T.; Bjöurkman, S.; Roth, B.; Fyge, Å.; Höuglund, P. Chirality 1995, 7, 44–52. 6 Simonyi, M. Med. Res. Rev. 1984, 4, 359–413. 7 Marshall, E. Science 1985, 229, 1071–1071. 8 Patocka, J.; Dworak, A. J. Appl. Biomed. 2004, 2, 95–100. 9 Srinivas, N. R.; Barbhaiya, R. H.; Midha, K. K. J. Pharm. Sci. 2001, 90, 1205–1215. 10 Asymmetric Synthesis, Academic P.; Morrison, J.D., Ed.: Orlando, 1983.

4

General Introduction

literature continues to grow at such a rate that comprehensive coverage is now impossible. 11 Initially, practical access to pure enantiomers relied largely on biochemical or biological methods. However, the scope of such methods using enzymes, cell cultures, or whole microorganisms is limited because of the inherent single-handed, lock-and-key specificity of biocatalysts. On the other hand, a chemical approach constitutes a complementary method, allowing for the flexible synthesis of a wide array of enantioenriched organic substances. The practical asymmetric synthesis features which should be fulfilled include high stereoselectivity, high rate and productivity, atom economy, cost efficiency, operational simplicity, environmental friendliness, and low-energy consumption. The decision of how to produce a molecule in enantiomerically pure form requires that the experimentalist balance the pros and cons of the available methods.12 One of the easiest ways would be to purchase the chiral compound, as this is a very convenient and fast method; however, the availability of some specific molecules is limited and moreover the cost, in many cases, is too high, especially for academic research labs, or they are just affordable in small quantities. Apart from that, the most important and widely used methods for this purpose are commented below: Ê Chiral pool: The convenience and time saving that implies the use of a commercially available chiral substrate makes it rarely cost effective to prepare it oneself, if the molecule is reachable at a reasonable price. However, it may not be so easy to find an appropriate compound to be purchased, for three main reasons, either the desired substructure does not yet exist, the price is beyond a laboratory’s means, or it is only affordable in small quantities. Ê Classical resolution: It can be a practical and scalable method with a great reproducibility, generally. But at the same time, it can be tedious either finding the right conditions for a successful resolution in certain cases, or the scale-up of the process. Besides, it is considered by many chemists as an inelegant method that generates to much waste since the unwanted enantiomer is discarded. 11 12

Gawley, R. E.; Aubé, J. In Principles of Asymmetric Synthesis; 2012; Vol. 1, pp 1–62. Gawley, R. E.; Aubé, J. In Principles of Asymmetric Synthesis; 2012; Vol. 2, pp 63–95.

5

General Introduction

Ê Chromatographic separation: It is an effective method on a small scale that affords both enantiomers directly. This could be useful when studying effect of chirality on a molecule’s biological activity. The drawback is that it is tiresome to validate and perform all the process with the inherent limitation of scalability, as large scale chromatographic separations are very expensive. Ê Kinetic resolution: This could be a robust synthetic method suitable for large scale preparations, as long as the separation of the product from the unreacted starting material is feasible. But here come along also the disadvantages of the classical resolution indicated above. Ê Chiral auxiliaries: They constitute a general tool for the synthesis of enantiomerically pure compounds, given the great amount of highly selective reactions mediated by them. The use of chiral auxiliaries in the total synthesis of natural products and biologically relevant molecules is widespread in the literature. Their cost and the inefficiency of having two additional steps are the main handicaps in this case. Ê Asymmetric catalysis: Performing a truly effective asymmetric catalyst is hard to beat, it would be the most elegant and efficient method. However, it can be hard to find the appropriate catalyst, if time is of the essence, the need to screen various catalysts for a new reaction can be a bottleneck. The choice of the last one as the best option was reinforced by the fact that in 2001, William S. Knowles, Ryoji Noyori and K. Barry Sharpless were awarded the Nobel Prize in Chemistry by the Royal Swedish Academy of Sciencies, for their great contribution in the development of asymmetric catalysis.13 Since then the field of asymmetric catalysis has evolved and grown exponentially. The novel asymmetric catalysis methodologies developed were effectively applied for preparing important structural motifs found in biologically active molecules. However, the difficulties in preparing substances enriched in a particular enantiomer persist because the number of catalytic enantioselective transformations available still remain limited. Therefore, the development of new 13

a) Knowles, W. S. Angew. Chem. Int. Ed. Engl. 2002, 41, 1999–2007. b) Noyori, R. Angew. Chem. Int. Ed. 2002, 41, 2008–2022. c) Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2024–2032.

6

General Introduction

methodologies of asymmetric catalysis is invariably of high interest. Taking into account that the symbiotic relationship between total synthesis and method development can continue to expand the understanding of catalysis on both fundamental and practical levels.14 0.1.2. ORGANOCATALYSIS Traditionally, the two pillars where asymmetric catalysis was sustained had been the use of enzymes and transition metal complexes bearing chiral ligands. The use of organic molecules as catalysts has only been documented sporadically over the past century, and those chemical studies were viewed more as unique chemical reactions than as integral parts of a larger, interconnected field.15 Finally in the late 1990s, things began to change when it was demonstrated that the use of small organic molecules as catalysts could be used to solve important problems in chemical synthesis. This trend was initiated by the use of enantiomerically pure ketones as catalysts for the asymmetric epoxydation of simple alkenes; 16 an briefly afterwards when the Strecker reaction was performed by hydrogen-bonding catalysis with organic compounds rather than with organometallic complexes.17 Eventually, the term organocatalysis was introduced to the chemical literature in 2000 by MacMillan and co-workers18 when they described a general activation strategy of iminium catalysis providing a more advantageous alternative for LUMO activation (Scheme 0.1.a). Simultaneously, it was published a complementary organocatalytic study by Barbas, Lerner and List19 on enamine catalysis (Scheme 0.1.b). They described that proline can perform as a novel amine-based asymmetric class I aldolase mimics showing that this simple a-amino acid catalysed the direct aldol reaction with comparable 14

Mohr, J. T.; Krout, M. R.; Stoltz, B. M. Nature 2008, 455, 323–332. a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621. b) U. Eder, G. Sauer and R. Wiechert, Angew. Chem., Int. Ed. Engl., 1971, 10, 496-497. 16 a) Tu, Y.; Wang, Z.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806–9807. b) Yang, D.; Yip, Y.C.; Tang, M.-W.; Wong, M.-K.; Zheng, J.-H.; Cheung, K.-K. J. Am. Chem. Soc. 1996, 118, 491– 492. c) Denmark, S. E.; Wu, Z.; Crudden, C. M.; Matsuhashi, H. J. Org. Chem. 1997, 62, 8288– 8289. 17 a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901–4902. b) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157–160. 18 Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243–4244. 19 List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396. 15

7

General Introduction

efficiency to the best organometallic catalyst,20 using similar mechanisms than enzymes to accomplish the HOMO activation. (a)

O

N

NH Bn (5 mol%) R

+

O

CHO R

MeOH-H 2O

R = alkyl, Ar

75-99% 84-93% ee endo:exo = 1:1

(b)

O

CO 2H N H (30 mol%)

O

+ H

R

O

DMSO

R = alkyl, Ar

OH R

54-97% 65-96% ee

Scheme 0.1. First organocatalytic reactions

Once the organocatalysis had been introduced, it emerged as a promising strategy in asymmetric catalysis. Its exponential growth in a very short period of time (Figure 0.2) converted organocatalysis in the third pillar of asymmetric synthesis, mainly due to the real advantages that this methodology offered to the scientific researchers. Among all its benefits, the main aspects are the savings in cost, time and energy, an easier experimental procedure, and reductions in chemical waste. Organic molecule catalysts are generally stable for being insensitive to oxygen and moisture in the air. A wide variety of them are often based on natural compounds, such as sugars, peptides or amino acids, which are available from biological sources as single enantiomers, so they are cheap to prepare and readily accessible in a range of quantities. Additionally,

small

organic

molecules

are

typically

non-toxic

and

environmentally friendly, unlike it happens with the most of the organometallic systems. Apart from that, organocatalysts can easily be linked to a solid support, making them useful for industrial applications. These features transformed organocatalysis into a complementary methodology to the 20

Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121, 4168–4178.

8

General Introduction

traditional and highly developed inorganic and biological approaches to asymmetric catalysis.21 1400

1164 1189 1154 1133

1200 1000

854 732

800

600

600

434

400 200 0

3

6

17

38

92

163

471

241

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Figure 0.2. The number of publications on organocatalysis since it was coined in the literature. Data were obtained by search of Scifinder in December 2015 for the keywords organocatalysis and organocatalyst, having been substracted the entries from “Abstract of Papers” and “Chemtracts” or with “No Corporate Source data available”.

Another relevant feature responsible for the success of organocatalysis was the identification of generic modes of catalyst activation, induction and reactivity. This consists of reactive species formed by the interaction of a single chiral catalyst with a principal functional group in a highly organized and predictable manner. Their value is that under this frame, it is a relatively straightforward issue to design new enantioselective reactions using these principles. From a mechanistic perspective, organocatalytic modes of activation can be classified according to two aspects, the first the covalent or noncovalent character of the substrate–catalyst interaction; and the second the chemical nature (Lewis base, Lewis acid, Brønsted base, Brønsted acid) of the organocatalyst.

22

It is important to keep in mind, however, that many

organocatalysts act through both covalent and noncovalent interactions and/or display a dual acid–base character, giving way to a group known as bifunctional catalysts.

21

a) List, B.; Yang, J. W. Science 2006, 313, 1584–1586. b) MacMillan, D. W. C. Nature 2008, 455, 304–308. 22 Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719-724.

9

General Introduction

Among

the

currently

operative

mechanisms

in

asymmetric

organocatalysis, the most important groups are aminocatalysis, carbene catalysis and Lewis base organocatalysis with covalent interactions; and hydrogen-bonding asymmetric

activation,

bifunctional

counteraction-directed

organocatalysis modes.

23

catalysis,

catalysis

within

phase-transfer the

and

noncovalent

Hereafter there will be mentioned the more

established modes for their length of standing and the more related ones to the current research work. a) Covalent organocatalysis AMINOCATALYSIS The term aminocatalysis has been coined 24 to designate reactions catalysed by primary and secondary amines. This field was discovered in the early 1970s15 but it remained as a laboratory curiosity for almost thirty years.18,19 Now, catalysis with chiral amines has become a well-established and powerful synthetic tool for the chemo- and enantioselective functionalisation of carbonyl compounds. In the last fifteen years, this field has grown at such a breathtaking pace that it is now recognized as an independent area of synthetic chemistry. 25 Among the multiple subparts this field can be classified, this memory will specifically be focused on the ones directly related with the present work.

¶ ENAMINE CATALYSIS One of the two first discovered methodologies19 in this field is the enamine catalysis, that has become one of the most intensively used organocatalytic modes of activation, allowing the functionalisation of carbonyl-

23

Moyano, A. In Stereoselective Organocatalysis; John Wiley & Sons, Inc.: Hoboken, New Jersey, 2013; pp 11–80. 24 List, B. Synlett 2001, 1675–1686. 15 a) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621. b) U. Eder, G. Sauer and R. Wiechert, Angew. Chem., Int. Ed. Engl., 1971, 10, 496-497. 18 Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243–4244. 19 List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc. 2000, 122, 2395–2396. 25 a) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem. Int. Ed. 2008, 47, 6138– 6171. b) List, B. Chem. Commun. 2006, 819-824.

10

General Introduction

containing compounds at the a-carbon in enantioselective manner (Scheme 0.2).26 O R'

+

E

Aminocatalysis

R

O E *

R'

R E = "C", "N", "O", "F", "S", "Cl", "Se", "Br", "I"

Scheme 0.2. Enantioselective a-functionalisation of enolizable carbonyl compounds with a huge variety of electrophiles

The

standard

catalytic

cycle

for

a

chiral

amine-catalysed

a-

functionalisation of a carbonyl compound is depicted in Scheme 0.3. A chiral, 2substituted pyrrolidine has been chosen as the most representative type of catalyst, acting together with an external Brønsted acid co-catalyst AH. The generalized enamine mechanism involves in the first step the acid-promoted condensation of the carbonyl with the amine to form an iminium ion. One of the a-acidic protons of the iminium ion is then removed by the conjugate base of the Brønsted acid A-, and the key nucleophilic enamine intermediate is formed. Reaction with the electrophile (generally protonated; the protonation can take place before or during this step) generates another iminium ion, whose hydrolysis liberates the product, the acid, and the amine catalyst, which can reenter the catalytic cycle. The Brønsted acid co-catalyst can be a protic solvent or an added external acid, or it can be a functional group present in the amine catalyst.

26

Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178-2189.

11

General Introduction O E

X N *

E

E * R

R

R' H 2O

X N *

A

R'

R

X N * H

H 2O

AH

O

AH +

R'

* R

X N *

A

R'

R' R X N *

AH + E

A

R'

EH

AH

R (E)-enamine

Scheme 0.3. Generalized mechanism for the enamine organocatalysis.

This reversible condensation of the chiral amine with carbonyl compounds leads to the formation of a positively charged iminium ion intermediate, mimicking the electronic situation of the p orbitals in Lewis acid catalysis (Scheme 0.4). On that intermediate, the energy of the lowest unoccupied molecular orbital (LUMO) of the system is effectively lowered, thus increasing the acidity of the a proton and consequently inducing the deprotonation at this position. Then, the enamine intermediate, considered as a nucleophilic enolate equivalent, is activated by the raising of the energy of the highest occupied molecular orbital (HOMO). R3 O

N H

R2

R1

R4

R3

N

R4

R1

- H+

R3

+ H+

R1

N

R1

LA

R2

O

LA

- H+ + H+

R1 R2

E

R2

R2 O

R4

O

LA E

R1 R2

Scheme 0.4. Comparison of the activation of carbonyl compounds by a Lewis acid (LA) in enamine aminocatalysis, known as HOMO catalysis.

12

General Introduction

Enaminic catalysis has been successfully employed both in addition reactions and in nucleophilic substitutions, with a great variety of electrophiles. Besides the aldolic condensation (Scheme 0.1.b), 27 there were subsequently developed diverse a-functionalisation reactions of aldehydes, Mannich

reactions,

29

enantioselective

a-amination

28

such as

reactions

with

azodicarboxylates, 30 hydroxylations with nitrosobenzene, 31 a-alkylations and arylations,32 a-halogenations (Cl, Br, I, F),33 and sulfenylations.34 In the Scheme 0.5. are shown a summary of the a-functionalisation of aldehydes by means of enamine catalysis.

27

a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 6798–6799. b) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752–1755. 28 Revisions about organocatalytic a-heterofunctionalisation of carbonylic compounds: a) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296–18304. b) Guillena, G.; Ramón, D. J. Tetrahedron: Asymmetry 2006, 17, 1465–1492. c) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2006, No. 19, 2001–2011. d) Ueda, M.; Kano, T.; Maruoka, K. Org. Biomol. Chem. 2009, 7, 2005-2012. 29 a) Córdova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C. F. J. Am. Chem. Soc. 2002, 124, 1866–1867. b) Ting, A.; Schaus, S. E. Eur. J. Org. Chem. 2007, 5797–5815. c) Verkade, J. M. M.; Hemert, L. J. C. van; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc. Rev. 2008, 37, 29–41. 30 a) Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292-4300. b) Duthaler, R. O. Angew. Chem. Int. Ed. 2003, 42, 975-978. c) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790-1793. d) List, B. J. Am. Chem. Soc. 2002, 124, 5656-5657. 31 a) Merino, P.; Tejero, T. Angew. Chem., Int. Ed. 2004, 43, 2995-2997. b) Palomo, P.; Vera, S.; Velilla, I.; Mielgo, A.; Gómez-Bengoa, E. Angew. Chem. Int. Ed. 2007, 46, 8054-8056. c) Kuarn, S.; Oelke, A. J.; Shaw, D. M.; Longbottom, D. A.; Ley, S. V. Org. Biomol. Chem. 2007, 5, 2678-2689. d) Zhong, G. Angew. Chem. Int. Ed. 2003, 42, 4247-4250. 32 a-Alkylations of aldehydes: a) Shaikh, R. R.; Mazzanti, A.; Petrini, M.; Bartoli, G.; Melchiorre, P. Angew. Chem. Int. Ed. 2007, 46, 8707-8710. b) Vignola, N.; List, B. J. Am. Chem. Soc. 2004, 126, 450-451. a-Arylations of aldehydes: c) Aleman, J.; Cabrera, S.; Maerten, E.; Overgaard, J.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2007, 46, 5520-5523. 33 a-Fluorination of aldehydes: a) Prakash, G. K. S.; Beier, P. Angew. Chem., Int. Ed. 2006, 45, 2172-2174. b) Pihko, P. M. Angew. Chem. Int. Ed. 2006, 45, 544-547. c) Shibatomi, K.; Yamamoto, H. Angew. Chem. Int. Ed. 2008, 47, 5796-5798. d) Steiner, D. D.; Mase, N.; Barbas III, C. F. Angew. Chem., Int. Ed. 2005, 44, 3706-3710. e) Beeson, T. D. MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 8826-8828. a-Chlorination of aldehydes: f) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc. 2004, 126, 4108-4109. g) Halland, N.; Braunton, A.; Bachmann, S.; Marigo, M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790-4791. aBromination of adehydes: h) Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton, A.; Jørgensen, K. A. Chem. Commun. 2005, 4821-4823. 34 a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jorgensen, K. A. Angew. Chem. Int. Ed. 2005, 44, 794-797. b) Enders, D.; Lüttgen, K.; Narine, A. A. Synthesis 2007, 959-980.

13

General Introduction

O HN H

PMP

CO 2Et R1 93-99% ee >10:1 d.r.

(ref. 29a)

O SR

H

N

R1

O

EtO 2C

N

H

(ref. 34a)

R

Ph

N

N

X

(ref. 33)

CO 2Et

EtO 2C

H

Halide source O

CO 2Et N NHCO 2Et R1 89-97% ee

(ref. 30c,d)

S

95-98% ee

H

PMP

N

N

(ref. 31d)

R1 enamine

O N

O

O

Ph

H

R1 X = F, Cl, Br up to 99% ee

R2

O

NHPh O

R1 94-99% ee (ref. 32c)

OH O H R1

OH 92-99% ee

R2

Scheme 0.5. a-Functionalisation of aldehydes via enamine activation.

Yet, at the same time, enamine catalysis has been used for conjugated additions of aldehydes to several Michael acceptors like nitroalkenes, 35 vinilketones, 36 ,28a maleimides, 37 phosphonates 38 and sulfones. 39 The more 35

a) Wang, W.; Wang, J.; Li, H. Angew. Chem. Int. Ed. 2005, 44, 1369–1371. b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem. Int. Ed. 2005, 44, 4212–4215. c) GarcíaGarcía, P.; Ladépêche, A.; Halder, R.; List, B. Angew. Chem. Int. Ed. 2008, 47, 4719–4721. d) Ruiz, N.; Reyes, E.; Vicario, J. L.; Badía, D.; Carrillo, L.; Uria, U. Chem. Eur. J. 2008, 14, 9357– 9367. 36 a) Melchiorre, P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151–4157. b) Peelen, T. J.; Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2005, 127, 11598–11599. 28a Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296–18304. 37 Zhao, G.-L.; Xu, Y.; Sunden, H.; Eriksson, L.; Sayah, M.; Cordova, A. Chem. Commun. 2007, 734-735. 38 Sulzer-Mossé, S.; Tissot, M.; Alexakis, A. Org. Lett. 2007, 9, 3749-3752.

14

General Introduction

representative examples of Michael type additions catalysed with proline or derivatives through an enamine activation are depicted in Scheme 0.6. R2

O

NO 2

H O

R1 99% ee up to 96:4 d.r.

R2 SO2R 3

H

R1 EWG up to 99% ee R2

O

(ref. 35c) (ref. 39)

NO 2

SO2R 3

COR 2

R

EWG

R1 92-95% ee

(ref. 36d)

R2

EWG = SO2R 4, CO 2R 4

COR 2

H

N H

O

(ref. 38)

PO(OR 2) 2

H R1

PO(OR 2)

2

PO(OR 2) 2 PO(OR 2) 2

46-97% ee

R1 enamine

(ref. 37)

O O

N

O

O

R2 N

H

O

R1 51-99% ee up to 15:1 d.r.

R2

Scheme 0.6. Conjugated additions of aldehydes to various Michael acceptors.

¶ IMINIUM CATALYSIS Together with enamine catalysis, iminium catalysis is the most prominent activation mode in asymmetric aminocatalysis,40 and the second of the first discovered methodologies. Initially, the proof of concept was done in a Diels Alder type reaction,18 and subsequently applied to carry out 1,3-dipolar cycloadditions,41 and afterwards extended to other reactions as Friedel-Crafts alkylations,

42

other

types

of

cycloadditions,

43

epoxidations,

44

39

a) Landa, A.; Puente, A.; Santos, J. I.; Vera, S.; Oiarbide, M.; Palomo, C. Chem. Eur. J. 2009, 15, 11954-11962. b) Landa, A.; Maestro, M.; Masdeu, C.; Puente, A.; Vera, S.; Oiarbide, M.; Palomo, C. Chem. Eur. J. 2009, 15, 1562-1565. c) Mossé, S.; Alexakis, A.; Mareda, J.; Bollot, G.; Bernardinelli, G.; Filinchuk, Y. Chem. Eur. J. 2009, 15, 3204-3220. 40 a) Enders, D.; Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15, 11058–11076. b) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470. c) Almaşi, D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299–365. d) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701–1716. 18 Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243–4244. 41 Jen, W. S.; Wiener, J. J. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 9874–9875. 42 a) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370–4371. b) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894–7895. c) Okamoto, A.; Kanatani, K.; Taiji, T.; Saito, I. J. Am. Chem. Soc. 2003, 125, 1172–1173.

15

General Introduction

cyclopropanations45 and especially Michael additions for a large number of nonmetallic nucleophilic moieties (Scheme 0.7).26 Now it is established as a general strategy for the asymmetric conjugate addition of nucleophiles at the b–position of conjugated carbonyl compounds. O R'

+

Nu

O

Aminocatalysis

R

R' R

*

Nu

Nu = "C", "H", "N", "O", "P", "S"

Scheme 0.7. Enantioselective b-functionalisation of a,b-unsaturated carbonyl compounds with a great variety of nucleophiles

The conventional catalytic cycle for a chiral pyrrolidine-catalysed bfunctionalisation of an a,b-unsaturated carbonyl compound is shown in Scheme 0.8, and it begins with the acid-promoted condensation of the carbonyl with the amine to form an unsaturated iminium ion, more electrophilic than the starting unsaturated carbonyl. This reactive intermediate suffers then the addition of the nucleophile at the b-position, leading to a,b-functionalised enamine in tautomeric equilibrium with an iminium ion. Hydrolysis of this intermediate releases both the product and the chiral ammonium salt, which can reenter the catalytic cycle.

43

a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 2458–2460. b) Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindhu, S.; Kirchhoefer, P. J. Am. Chem. Soc. 2003, 125, 2058–2059. c) Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 11616–11617. 44 a) Lee, S.; MacMillan, D. W. C. Tetrahedron 2006, 62, 11413-11424. b) Marigo, M.; Franzén, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 6964-6965. 45 Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240-3241. 26 Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178-2189.

16

General Introduction

H

X N * H

AH +

O

O

R'

R'

R * Nu H 2O

A

R

X N * H2

H 2O

X N *

A H

A

X N *

R'

R'

R * Nu

unsaturated iminium ion

R X N *

NuH

R'

AH

AH

R * Nu

Scheme 0.8. Generalized mechanism for the chiral amine-catalysed b– functionalisation of a,b-unsaturated carbonyls.

In this case, the reversible condensation of a chiral amine with carbonyl conjugated systems leads to the formation of an iminium cation intermediate. Here the electronic redistribution facilitates nucleophilic additions, which might emulate the equilibrium dynamics and p-orbital electronics that are inherent to Lewis acid catalysis (Scheme 0.9). In this way, it is said that there is a LUMO activation due to its lowering at the iminium salts, making them more electrophilic than the corresponding carbonyl compounds and more reactive toward nucleophilic attacks. R3 O R1

R2

O R1

N H

R4

R3

R4

R1

LA

R2

N

R2

O R1

Nu

LA

Nu

R2

Scheme 0.9. Comparison of the activation of conjugated carbonyl compounds by a Lewis acid (LA) in iminium aminocatalysis, known as LUMO catalysis.

17

General Introduction

Employing this activation via the iminium ion, there have been developed a great variety of conjugate addition reactions with diverse chiral catalysts bearing a secondary amine.40 This organocatalytic methodology has a really wide scope (Scheme 0.10), it has been applied, for example, in additions of malonates

46

or nitroalkanes

47

to conjugated aldehydes and ketones,

enantioselective reductions of b,b-disubstituted a,b-unsaturated aldehydes,48 or 1,4-additions of sulfur-,49 nitrogen-50 and oxygen-derivatives.51

46

For additions to enones: a) Halland, N.; Aburel, P. S.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2003, 42, 661–665. b) Knudsen, K. R.; Mitchell, C. E. T.; Ley, S. V. Chem. Commun. 2006, 44, 66–68. For additions to aldehydes: c) Brandau, S.; Landa, A.; Franzén, J.; Marigo, M.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2006, 45, 4305–4309. 47 a) Prieto, A.; Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897–3900. b) Mitchell, C. E. T.; Brenner, S. E.; García-Fortanet, J.; Ley, S. V. Org. Biomol. Chem. 2006, 4, 2039–2049. 48 a) Yang, J. W.; Fonseca, M. T. H.; Vignola, N.; List, B. Angew. Chem. Int. Ed. 2005, 44, 108110. b) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 32-33. 49 Marigo, M.; Schulte, T.; Franzén, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 1571015711. 50 a) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328–9329. b) Dinér, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew. Chem. Int. Ed. 2007, 46, 1983– 1987. c) Uria, U.; Vicario, J. L.; Badía, D.; Carrillo, L. Chem. Commun. 2007, 2509–2511. d) Lin, Q.; Meloni, D.; Pan, Y.; Xia, M.; Rodgers, J.; Shepard, S.; Li, M.; Galya, L.; Metcalf, B.; Yue, T.Y.; Liu, P.; Zhou, J. Org. Lett. 2009, 11, 1999–2002. 51 Bertelsen, S.; Dinér, P.; Johansen, R. L.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 1536–1537.

18

General Introduction R 3O 2C

R2 H 86-95% ee

Ph O

N

CO 2R 3 O

(ref. 46c)

O

HO

R2 H 89-97% ee

CO 2R 3 CO 2R 3

N Ph

N

R3

N

R4

O

N H

R2 H up to 99% ee

R2 R1 up to 91% ee

NO 2 R3

NO 2 R4O

R4

R1

R4

(ref. 50)

(ref. 47b)

R

(ref. 51)

R3

R3

R2

(ref. 48)

R5

iminium

EtO 2C R4

R 3 SH

R5

H H CO 2Et N H

R4

O

R2 H 90-97% ee

(ref. 49)

SR3 O R2 H 89-97% ee

Scheme 0.10. Selection of b-functionalisation of conjugated carbonylic compounds.

In most cases of organocatalysis based on iminium-activation, involving the most generalized secondary-amine catalysts, the Michael acceptor is an a,b-unsaturated aldehyde, since the generation of the iminium intermediate is more efficient with enals than with a,b-unsaturated ketones. That is due to the greater steric hindrance of ketones in both sides of the carbonylic group, leading to a poorer geometric control of the iminium intermediate (lower enantioselectivities) or even preventing the possibility of its formation (Figure 0.3.a). To avoid this problem, there have been developed primary-amine organocatalysts, 52 which allow a facile condensation between the enone and the aminocatalyst and also a better geometrical regulation given the bigger difference between the coplanar substituents of the double bound C=N of the iminium ion (Figure 0.3.b).

52

a) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759–1772. b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047. c) Peng, F.; Shao, Z. J. Mol. Catal. A Chem. 2008, 285, 1–13. d) Xu, L.W.; Luo, J.; Lu, Y. Chem. Commun. 2009, 1807-1821. e) Jiang, L.; Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354-365.

19

General Introduction (a)

(b) H H H

H H

N R1

H N R1

R2

H

H

R2

R2

H

N R1

R1

N H R2

Figure 0.3. Geometric control in the iminium intermediates of secondary and primaryamine organocatalysts with a,b-unsaturated ketones.

Some other relevant mechanisms of covalent organocatalysis that won’t be discussed here, for not being so prevalent or related with the current research work, are the dienamine catalysis, the SOMO catalysis or photoredox methodologies among others. b) Noncovalent organocatalysis As noncovalent organocatalysts, there will be included those which will activate the reaction substrate through some weaker interactions different than the covalent ones, inter alia, hydrogen-bonding, direct electrostatic activation and p interactions. 53 While, in some cases, this activation will occur directly between the catalyst and the substrate, in others, the organocatalyst may react previously with the starting material or with a co-catalyst (for instance, through acid-base reactions), to give rise to an intermediate that will be the responsible for the asymmetric induction of the reaction. Apart from that, it should be noted that these noncovalent interactions can take place by their own or together with some covalent activation, and in the latter case the reactivity and the enantioselectivity of the organic reaction would probably be improved.54 Thus, depending on the degree of proton transfer in the transition state, one may distinguish between hydrogen-bonding catalysis (when the hydrogen is still covalently bonded to the catalyst) and Brønsted acid catalysis (complete 53

a) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134–2136. b) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem. Int. Ed. 2005, 44, 4032–4035. c) Hamza, A.; Schubert, G.; Soós, T.; Pápai, I. J. Am. Chem. Soc. 2006, 128, 13151–13160. d) Kótai, B.; Kardos, G.; Hamza, A.; Farkas, V.; Pápai, I.; Soós, T. Chem. Eur. J. 2014, 20, 5631–5639. e) Holland, M. C.; Metternich, J. B.; Daniliuc, C.; Schweizer, W. B.; Gilmour, R. Chem. Eur. J. 2015, 21, 10031–10038. f) Wang, L.; Chen, J.; Huang, Y. Angew. Chem. Int. Ed. 2015, 54, 15414–15418. For analysis of noncovalent interactions in organocatalysis: g) Inokuma, T.; Furukawa, M.; Uno, T.; Suzuki, Y.; Yoshida, K.; Yano, Y.; Matsuzaki, K.; Takemoto, Y. Chem. Eur. J. 2011, 17, 10470–10477. h) Holland, M. C.; Berden, G.; Oomens, J.; Meijer, A. J. H. M.; Schäfer, M.; Gilmour, R. Eur. J. Org. Chem. 2014, 5675–5680. 54 Mathew, S. P.; Klussmann, M.; Iwamura, H.; Wells, Jr., D. H.; Armstrong, A.; Blackmond, D. G. Chem. Commun. 2006, 4291-4293.

20

General Introduction

proton transfer from the catalyst to the substrate), but logically several intermediate situations are possible (Figure 0.4).55 However, the term hydrogenbonding activation is generally used to represent both hydrogen-bonding catalysis and Brønsted acid catalysis. A H

B

A

weak hydrogen bond BH bond lenghth >2.2 Å bond energy 98:2 d.r.

S Bn

N

N H

O

N H

CO 2R

R2

PhCO 2H (1.25-2.5 mol%) DCM, 45ºC

O

N

NH 2

(b) N

CO 2Me

N

Computer-aided OC (5 mol%) PhCO 2H (2.5 mol%) DCM, 50ºC, 96h

O

O 83% 97% ee >98:2 d.r.

S N H

N H

CO 2Me

NH 2

Scheme 2.6. Desymmetrization by intramolecular Michael reaction to conjugated esters.

There

have

enantioselective 194

also

been

1,4-additions

of

reported

several

carbon-centred

guanidine-catalysed

nucleophiles

to

a,b-

Gammack Yamagata, A. D.; Datta, S.; Jackson, K. E.; Stegbauer, L.; Paton, R. S.; Dixon, D. J. Angew. Chem. Int. Ed. 2015, 54, 4899–4903.

134

Chapter 2

Background

unsaturated esters, thioesters and amides. 195 For instance, an unsaturated lactone underwent Michael addition with a 1,3-dithiomalonate to give the desired product with good yield and excellent enantioselectivity in the presence of a catalytic amount of a chiral bicyclic guanidine (Scheme 2.7.). O O O

O

+ R

R=S

Guanidine (20 mol%)

O R

O

PhMe, -50ºC tBu

N N H

N

tBu

COR ROC 85%, 96% ee

Scheme 2.7. Asymmetric Michael addition to an unsaturated furanone.

2.1.2. AZA-MICHAEL REACTIONS WITH ESTER DERIVATIVES AS MICHAEL ACCEPTORS Finally, regarding aza-Michael reactions there are really few examples with a,b-unsaturated esters or thioesters. On the one hand, Weiß et al reported in 2012 a proof of concept for the asymmetric aza-Michael addition with readily available alkyl enoate as substrate in the presence of a chiral phase-transfer catalyst (PTC), leading to the enantioenriched adduct. However, the asymmetric induction remained limited to enantiomeric excesses of up to 37% (Scheme 2.8). 196 The electrophilicity of the Michael acceptor is enhanced by adding a CF3-substituent at the b-position, whereas the N-nucleophile is activated by the a-effect of the alkoxy group.94 Furthermore, it is necessary the addition of a stoichiometric amount of a basic solution to the reaction mixture.

195

Chiral Guanidines in Michael Reactions, Nájera, C.; Yus, M. Springer Berlin Heidelberg: Berlin, Heidelberg, 2015; pp. 1–34 and references therein. 196 Weiß, M.; Borchert, S.; Rémond, E.; Jugé, S.; Gröger, H. Heteroat. Chem. 2012, 23, 202– 209. 94 Heaton, M. M. J. Am. Chem. Soc. 1978, 100, 2004–2008.

135

Chapter 2

O

Background

N H

Boc +

PTC (25 mol%) KOH aq. (50%, 1.2 equiv.)

O F 3C

OEt

O

toluene, -20ºC, 23h F.

F 3C

F

N *

Boc CO 2Et

81%, 37% ee

F N Br F F

F

Scheme 2.8. Aza-Michael addition to conjugated esters with an alkoxy carbamate.

Matsubara and Asano reported also two isolated examples of intramolecular aza-Michael additions of aniline carbamates to conjugated thioesters

by

means

of

bifunctional

quinine-derived

amino(thio)urea

catalysts.128g The corresponding 2-substituted indolines were prepared with moderate yields and enantioselectivities (Scheme 2.9).

SAr NH Cbz

O

Amino(thio)urea (10 mol%)

S O

mesitylene, 25ºC OMe N

H

HN HN Ar

X

N

N Cbz 80%, 55% ee 90h, X=O

S

or

O N Cbz 32%, 69% ee 24h, X=S

Ar = 3,5-(CF3) 2-Ph

Scheme 2.9. Asymmetric IMAMR with a,b-unsaturated thioesters to synthesize indolines.

On the other hand, Bandini and Umani-Ronchi published in 2008111,197 the first and only direct protocol until the moment198 for aza-Michael additions to a,b-unsaturated esters. As it consists on an intramolecular aza-Michael 128g

Miyaji, R.; Asano, K.; Matsubara, S. Org. Lett. 2013, 15, 3658–3661. For theoretical studies: Bandini, M.; Bottoni, A.; Eichholzer, A.; Miscione, G. Pietro; Stenta, M. Chem. Eur. J. 2010, 16, 12462–12473. 111 Bandini, M.; Eichholzer, A.; Tragni, M.; Umani-Ronchi, A. Angew. Chem. Int. Ed. 2008, 47, 3238–3241. 198 There have been also used b-keto-esters for IMAMR, but in those cases the enone was the Michael acceptor, activated by the ester at the b-position, which was subsequently removed (Scheme 1.16). a) See ref. 112: Z. Feng, Q.-L. Xu, L.-X. Dai and S.-L. You, Heterocycles, 2010, 80, 765. b) See ref. 113: Liu, X.; Lu, Y. Org. Lett. 2010, 12, 5592–5595. c) Xiao, X.; Liu, X.; Dong, S.; Cai, Y.; Lin, L.; Feng, X. Chem. Eur. J. 2012, 18, 15922–15926. 197

136

Chapter 2

Background

reaction, it has already been mentioned in the corresponding section in Chapter 1. However, given the relevance in this conjugate esters branch, it has been newly referred. Here the indole nitrogen is added to a,b-unsaturated esters affording tricycles with good yields and enantioselectivities by means of phase transfer catalysis with a chiral ammonium salt of cinchonidine derivative (Scheme 2.9). HO

N

Br

X CF3

Y

O

N H

O N Z

RO X = H, F, Cl OMe, Me Y = H, C6H 5, β-naphtyl Z = Bn, PMP R = Et, Me, tBu

N

X Y

(10 mol%)

KOH aq., toluene 0ºC to -45ºC

O

O

N N

RO

Z

55-93% 53-90% ee

Scheme 2.9. Aza-Michael addition to conjugated esters with an indolic nitrogen.

In addition, Takemoto’s group described, for the first time, the use of aminoboronic acids as efficient catalysts for the direct intramolecular heteroMichael addition of a,b-unsaturated carboxylic acids. 199 Furthermore, they developed an asymmetric version of this protocol using a dual catalytic system composed of an aminothiourea and an arylboronic acid allowing the successfully synthesis of the desired heterocycles in high yields and ee’s (Scheme 2.1.a). The overall utility of this protocol was demonstrated by a onepot enantioselective synthesis of (+)-Erythrococcamide B, which proceeded via sequential Michael and amidation reactions (Scheme 2.1.b).

199

Azuma, T.; Murata, A.; Kobayashi, Y.; Inokuma, T.; Takemoto, Y. Org. Lett. 2014, 16, 4256– 4259.

137

Chapter 2

(a)

Background

Boronic acid (20 mol%) Aminothiourea (20 mol%)

XH

R

R

OH

( )n

( )n

MTBE/CCl 4 (1:2), MS 4Å r.t., 24-120 h

O X = O, NTs R = H, Me, Br, MeO n = 0, 1

B(OH) 2 MeO F 3C

(b) O

X

N Me H

N H

Boronic acid (20 mol%) Aminothiourea (20 mol%)

OH OH

O

MTBE/CCl 4 (1:2), MS 4Å r.t., 24 h

O

H N

O

O

iBu

O

25-98% 50-96% ee

S

CF3

OH

NH 2

O

O

OH O

O 94%, 94% ee iBuNH 2 50ºC, 48h

O

O

62%, 94% ee (+)-Erythrococcamide B

Scheme 2.10. Construction of asymmetric heterocyclic compounds with intramolecular hetero-Michael reactions with a,b-unsaturated carboxylic acids as electrophiles.

2.1.3. ORGANOCATALYTIC INTRAMOLECULAR AZA-MICHAEL REACTIONS IN DOMINO PROCESSES The ability to create complex molecules in only a few steps has long been the dream of chemists. Now, with the development of domino reactions, the dream has become almost true for the laboratory chemist, at least partly. In addition, this kind of transformations are frequently used not only in basic research but also in applied chemistry.200 Nowadays, the main issue is the efficiency of a synthesis, which can be defined as the increase of complexity per transformation. Notably, modern syntheses must obey the needs of our environment, which includes the preservation of resources and the avoidance of toxic reagents as well as toxic

200

a) Tietze, L. F. Chem. Rev. 1996, 96, 115–136. b) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem. Rev. 1996, 96, 195–206. c) Tietze, L. F.; Brasche, G.; Gericke, K. M. In Domino Reactions in Organic Synthesis; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2006. d) Enders, D.; Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007, 46, 1570–1581.

138

Chapter 2

Background

solvents.201 Such an approach has advantages not only for Nature but also in terms of economics, as it allows reductions to be mad in production time as well as in the amounts of waste products. For a long time, the general procedure for the synthesis of organic compounds has been a stepwise formation of individual bonds in the target molecules, with work-up stages after each transformation. In contrast, the denominated domino reactions202 would comprise transformations of two or more bond-forming reactions under identical reaction conditions, in which the latter transformations take place at the functionalities obtained in the formerbond constructing reactions. Inside classification of domino processes, the anionic domino reactions are the most often encountered in the chemical literature, being included in this group those where the primary step in the process is the attack of either an anion or a pseudo anion, as an uncharged nucleophile, onto an electrophilic center. Therefore, transformations such as Michael addition, aldol reactions or peptide couplings can be included in this category. Concretely,

organocatalytic

intramolecular

aza-Michael

reactions

(IMAMR) have been involved in several domino processes, such as the sequences

IMAMR/

alkylation,

203

aza-Morita-Baylis-Hillman/

IMAMR,135

Mannich/ IMAMR,204 aminoxylation/ IMAMR,205 or hydroxylation/ IMAMR.206 As 201

a) Sheldon, R. a. Pure Appl. Chem. 2000, 72, 1233–1246. b) Sheldon, R. a. Green Chem. 2005, 7, 267-278. 202 The word tandem is often used to describe this type of process, but it is less appropriate as the encyclopedia defines tandem as “locally, two after each other”, as on a tandem bicycle. Thus, the term tandem does not fit so well with the time-resolved aspects of the domino reaction type. For a proper example of a tandem reaction, where individual transformations of independent functionalities take place under the same reaction conditions, see: Roush, W. R.; Sciotti, R. J. J. Am. Chem. Soc. 1998, 120, 7411–7419. 135 Takizawa, S.; Inoue, N.; Hirata, S.; Sasai, H. Angew. Chem. Int. Ed. 2010, 49, 9725–9729. 203 Guo, J.; Yu, S. Org. Biomol. Chem. 2015, 13, 1179–1186. 204 a) Enders, D.; Goddertz, D. P.; Beceno, C.; Raabe, G. Adv. Synth. Catal. 2010, 352, 28632868. b) Yang, H.; Carter, R. G. J. Org. Chem. 2009, 74, 5151-5156. c) Rueping, M.; Azap, C. Angew. Chem. Int. Ed. 2006, 45, 7832-7835. d) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2003, 5, 4301–4304. e) Itoh, T.; Yokoya, M.; Miyauchi, K.; Nagata, K.; Ohsawa, A. Org. Lett. 2006, 8, 1533–1535. f) Khaliel, S.; Nandakumar, M. V.; Krautscheid, H.; Schneider, C. Synlett. 2008, 2705-2707. g) See Ref. 96: Sundén, H.; Ibrahem, I.; Eriksson, L.; Córdova, A. Angew. Chem. Int. Ed. 2005, 44, 4877–4880. 205 a) Lu, M.; Zhu, D.; Lu, Y. P.; Hou, Y. X.; Tan, B.; Zhong, G. F. Angew. Chem. Int. Ed. 2008, 47, 10187-10191. b) Zhu, D.; Lu, M.; Chua, P. J.; Tan, B.; Wang, F.; Yang, X.; Zhong, G. Org. Lett. 2008, 10, 4585-4588. 206 Yamamoto, Y.; Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5962–5963.

139

Chapter 2

Background

noted, most of the cases have the IMAMR as the second step of the sequence, what makes especially sense when a,b-unsaturated esters are the Michael acceptors, because the previous reaction will be generating a more nucleophilic intermediate able to react with those less electrophilic moieties. Activated ester equivalents have been involved in two examples of organocatalytic domino sequences with IMAMR. On the one hand, Schneider’s group reported in 2008204f a proline-catalysed domino Mannich/ aza-Michael reaction of chiral 7-oxo-2-enimides containing an aldehyde moiety tethered to an a,b-unsaturated oxazolidinone with glyoxyl imines to furnish highly substituted pipecolic esters in moderate yields and excellent stereocontrol (Scheme 2.11). Throughout this process two new s bonds and three new stereogenic centers are formed as a single stereoisomer as it was already demonstrated by Barbas and co-workers for similar Mannich reactions.29 R1

O H 1. Mannich R 2O 2C

1. L-proline (20 mol%) DMF, -20ºC

+

N PMP O 2. IMAMR

O N

O

2. NaBH(OAc) 3 .

R1 HO R 2O 2C

O N PMP

Bn

R1 = H, alkyl R 2 = alkyl

O N

O

Bn

46-56%

Scheme 2.11. Domino Mannich/ IMAMR to an activated ester surrogate

On the other hand, a,b-unsaturated diesters where involved in an asymmetric organocatalytic domino aminoxylation/ aza-Michael reaction for the synthesis of multifunctionalised tetrahydro-1,2-oxazines.207 The C-O/ C-N bond formations are achieved in moderate to good yields with excellent diastereo(99% ee) by means of L-proline catalyst (Scheme 2.12).

207

Zhu, D.; Lu, M.; Chua, P. J.; Tan, B.; Wang, F.; Yang, X.; Zhong, G. Org. Lett. 2008, 10, 4585–4588.

140

Chapter 2

Background

O

1. Aminoxylation CO 2R1

O

R1 O 2C

R2

N L-Proline (10 mol%)

+

CH3CN, -20ºC

R2

2. IMAMR R1 = alkyl

OHC

CO 2R1

CO 2H

N H

R 2 = H, Me, Cl, Br, OPh

CO 2R1

O N

52-84% 92-99% ee >99:1 d.r.

Scheme 2.12. Asymmetric domino aminoxylation/ IMAMR which conjugated diesters.

In addition, Enders and co-workers reported an efficient domino Mannich/aza-Michael reaction204a between N-protected aryl aldimines and gmalonate-substituted a,b-unsaturated methyl esters promoted by a bifunctional thiourea

catalyst.

This

methodology

furnishes

2,5-cis-configured

polyfunctionalised pyrrolidines in good to excellent yields, enantioselectivities and excellent diastereoselectivities (Scheme 2.13). They initially intended to perform the same protocol with simple conjugated esters but that Michael acceptor nature was not sufficiently electrophilic to enable a direct subsequent aza-Michael addition with the generated secondary amine. CF3

2. Intrarmolecular aza-Michael CO 2Me

S F 3C

PG

MeO 2C CO 2Me

+

N H

N H

(10 mol%)

N Ar

DCM

MeO 2C 1. Intermolecular Mannich

MeO 2C NMe 2

PG

CO 2Me

N

Ar CO 2Me MeO 2C 76-99% 75-94% ee

Scheme 2.13. Asymmetric synthesis of pyrrolidines through a domino Mannich/ IMAMR with conjugated diesters.

Apart from that, there have been also described some IMAMR to conjugated esters in organocatalysed domino processes, generally for the preparation of benzofused scaffolds. 208 Enders published in 2008 the first catalytic asymmetric synthesis of 1,3-disubstituted isoindolines, based on a metal-free one-pot Brønsted acid catalysed Friedel-Crafts/ base-catalysed aza-

208

The following transformations described in Schemes 2.14-16 have already been partially discussed in the benzofused heterocycles Section 1.1.2., at Schemes 1.22, 28-29 in tetrahydroisoquinolines and isoindolines subsections, respectively.

141

Chapter 2

Background

Michael addition reaction of bifunctional e-iminoenoates and indoles.136 Chiral BINOL-derived N-triflyl phosphoramides catalysed the initial Friedel-Crafts reaction and the isoindoline products were obtained in high yields and excellent diastereo- and enantiomeric ratios (Scheme 2.14). R1

1. Friedel-Crafts

NTs R3

R1 Brønsted acid (10 mol%) DCM, r.t.

+ N R2 R1

2. IMAMR

= H, Br, OMe, CO 2Me R 2 = H, Me

CO 2R 4

R3

= H, F R 4 = Me, tBu

then DBU (50 mol%) .

N

R2

R3 N Ts

4-(NO 2)C 6H 4

O O

P

CO 2R 4

O NHTf

4-(NO 2)C 6H 4

71-99% 61:39-95:5 e.r. ≥9:1 d.r.

Scheme 2.14. One-pot Friedel-Crafts/ IMAMR with e-iminoenoates.

Sasai and co-workers137 described the enantioselective synthesis of insoindolines,

through

an

organocatalysed

aza-Morita-Baylis-

Hillman/intramolecular aza-Michael reaction of a,b-unsaturated esters and Ntosylimines promoted by the chiral acid-base catalyst (S)-2-diphenylphosphanyl[1,1’]binaphtalenyl-2-ol. This procedure easily accessed to afford 1,3disbustitued isoindolines in good yields with excellent diastereo- and enantioselectivities (Scheme 2.15). 209

136

Enders, D.; Narine, A. A.; Toulgoat, F.; Bisschops, T. Angew. Chem. Int. Ed. 2008, 47, 5661–5665. 137 Takizawa, S.; Inoue, N.; Hirata, S.; Sasai, H. Angew. Chem. Int. Ed. 2010, 49, 9725–9729.

142

Chapter 2

Background O R2

O

N

+

R1

R1

OC (10 mol%)

Ts CO 2R 3

R2 N Ts

CHCl3, 10ºC

R1

CO 2R 3

OH PPh 2

= Me, Et, Ph, H, OPh R 2 = H, 5-Me, 5-F, 5-Cl, 6- Cl R 3 = Me, Et, Bn

49-98% 68-93% ee

1. aza-MBH R1 R2

R1 LB

O

*

N Ts

O

*

BA

2. IMAMR

R2

LB

* NTs

* CO 2R 3

*

BA

CO 2R 3

Scheme 2.15. aza-MBH/intramolecular aza-Michael addition domino reaction.

A domino strategy consisting of a reductive amination/ aza-Michael addition sequence was successfully applied by Enders et al. for the asymmetric synthesis of trans-1,3-disubstituted tetrahydroisoquinolines.127 Using a chiral phosphoric

acid

as

an

organocatalyst

and

a

biphenyl-substituted

benzothiazoline as hydride source, they reacted p-anisidine with keto enoates to yield the reductive amination intermediates, that would suffer the IMAMR to reach the final products (Scheme 2.16.a). Notably, an indole-derived transdisubstituted b-carboline was also obtained with this three-component sequence in excellent yield and stereoselectivity (Scheme 2.16.b). 210

127

Enders, D.; Liebich, J. X.; Raabe, G. Chem. Eur. J. 2010, 16, 9763–9766.

143

Chapter 2

Background

(a) R1

Phosphoric acid (10 mol%) Benzothiazoline p-anisidine

O R2 O

R1 = 4-MeO, 4,5-(OCH2O); 2 R = OtBu, N

O

N

O CO 2tBu

tBuOK THF, r.t.

m-tylene, 45ºC 5Å M.S. . O O

P

O OH

N R2

2. IMAMR O

S N H

Phosphoric acid (10 mol%) Benzothiazoline p-anisidine m-tylene, 45ºC 5Å M.S. .

1. Reductive amination PMP

81-97% 93-98% ee d.r. > 95.5

Ar

Ar Ar = 2,4,6,-(iPr) 3Ph

(b)

R1

N PMP tBuOK THF, r.t.

N

CO 2tBu

85% 94% ee d.r. > 95.5

Scheme 2.16. Reductive amination/ IMAMR with a,b-unsaturated esters.

Finally, in 2014 has been published an elegant synergistic catalytic system comprising a ruthenium complex with a chiral Brønsted acid for an enantioselective four-component Mannich/cascade aza-Michael reaction. 211 The ruthenium-associated ammonium ylides successfully trapped with in situ generated imines indicates a septwise process of proton transfer in the ruthenium catalysed carbenoid N-H insertion reaction. This transformation features a mild, rapid, and efficient method to synthesize 1,3,4-tetrasubstitued tetrahydroisoquinolines bearing a quaternary stereogenic carbon center from simple starting precursors in moderate yields with high diastereo- and enantioselectivity (Scheme 2.17).

211

Jiang, J.; Ma, X.; Ji, C.; Guo, Z.; Shi, T.; Liu, S.; Hu, W. Chem. Eur. J. 2014, 20, 1505–1509.

144

Chapter 2

Background

O CO 2R1

+

Ar1NH 2

OR*

P

N2 Ar2

chiral Brønsted acid OR*

O H Ar1 O N

CO 2CH3

2. tBuOK . .

Ar2

H Cbz N OCH3

ORuLn 1. Mannich

4-CF3Ph O

P

Ar2 Cbz

CO 2R1

O OH

4-CF3Ph

H 3CO 2C

ammonium ylide trapping

NHAr1 CO 2CH3 N

O

ruthenium complex H

CO 2R1

1. [RuCl 2(p-cymene)] (1 mol%) Phosphoric acid (10 mol%) (±)-mandelic acid (10 mol%)

CbzNH 2

Ar2 NHCbz N H

Ar1

CO 2R1

2. IMAMR base cascade reaction

Ar1

NH

CO 2CH3 Ar2 NCbz

CO 2R1

Scheme 2.17. Asymmetric Mannich/ IMAMR cascade with a,b-unsaturated-esters.

2.1.4. CONJUGATED ESTER SURROGATES AS ACCEPTORS IN MICHAEL-TYPE REACTIONS As it has been seen, a,b-unsaturated esters are poor Michael acceptors and their application in organocatalysed conjugated additions is compromised by their low reactivity. This problem can be overcome by using activated ester surrogates, which facilitate the activation of the electrophilic moiety. In the literature there can be found several functional groups acting as ester equivalents, such as fluorinated derivatives (a), 212 acyl oxazolidinones (b), 213 pyrrolidinone (c),213 imides (d),214 phosphonates (e),215 pyrroles (f),216 pyrazoles

212

Fang, X.; Dong, X.-Q.; Liu, Y.-Y.; Wang, C.-J. Tetrahedron Lett. 2013, 54, 4509–4511. For oxazolidinones: a) Evans, D. a; Scheidt, K. a; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001, 123, 4480–4491. b) Hird, A. W.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 1276–1279. c) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem. Commun. 2001, 1240– 1241. d) Kanemasa, S. J. Synth. Org. Chem. Japan 2003, 61, 1073–1080. e) See Ref. 204f: Khaliel, S.; Nandakumar, M.; Krautscheid, H.; Schneider, C. Synlett 2008, 2705–2707. For : pyrrolidinones: f) See Ref 53b Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem. Int. Ed. 2005, 44, 4032–4035. For both of them: g) See Ref. 53a: Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124, 2134–2136. h) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263–3296. i) Zhang, W.; Tan, D.; Lee, R.; Tong, G.; Chen, W.; Qi, B.; Huang, K.W.; Tan, C.-H.; Jiang, Z. Angew. Chem. Int. Ed. 2012, 51, 10069–10073. 214 a) Goodman, S. N.; Jacobsen, E. N. Adv. Synth. Catal. 2002, 344, 953–956. b) Sammis, G. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 4442–4443. c) Sibi, M. P.; Prabagaran, N.; Ghorpade, S. G.; Jasperse, C. P. J. Am. Chem. Soc. 2003, 125, 11796–11797. d) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959–8960. e) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204–11205. f) Sallio, R.; Lebrun, S.; Schifano-Faux, N.; Goossens, J. F.; Agbossou-Niedercorn, F.; Deniau, E.; Michon, C. Synlett 2013, 24, 1785– 1790. 213

145

Chapter 2

Background

(g)213d,217 and pyrazolidinones (h).218 In addition, there have been also added extra functionalities to enhance the conjugated ester’s electrophilicity, such as an extra ester group at the geminal carbon 219 (i) or an a-keto residue 220 (j) (Figure 2.1). EWG

R

O

CF3 O

O N

CF3

(a) O

O

O N

O

(b)

O

O

N

N

(f)

(g)

N

R' (h)

R'

CO 2R'

O P

R'O

(d) O

N N

O

O N H

(c)

O

O

OR'

(e)

O

CO 2R' (i)

CO 2R' ( j)

Figure 2.1. Ester equivalents used to activate the Michael acceptor.

Given the relevance in the present memory, there will pointed out some examples containing a,b-unsaturated N-acyl pyrazole as electrophiles in conjugate additions. Sibi described in 2007217b an efficient conjugate hydroxyl amine addition to enoates that proceed with high levels of enantioselectivity using a bifunctional organocatalyst. Overall, it was achieved good substrate scope for the addition of amines to pyrazole derived enoates using a thiourea 215

a) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125, 10780–10781. b) Bachu, P.; Akiyama, T. Chem. Commun. 2010, 46, 4112-4114. c) Jiang, H.; Paixão, M. W.; Monge, D.; Jørgensen, K. A. J. Am. Chem. Soc. 2010, 132, 2775– 2783. 216 a) Lee, S. D.; Brook, M. A.; Chan, T. H. Tetrahedron Lett. 1983, 24, 1569–1572. b) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada, S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559–7570. c) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem. Int. Ed. 2005, 44, 4365–4368. d) Evans, D. A.; Borg, G.; Scheidt, K. A. Angew. Chem. Int. Ed. 2002, 41, 3188–3191. 217 a) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394–13395. b) See Ref. 106: Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007, 129, 8064-8065. c) See Ref. 74b: Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615–6616. d) Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Adv. Synth. Catal. 2012, 354, 1141–1147. e) Dong, X.-Q.; Fang, X.; Tao, H.-Y.; Zhou, X.; Wang, C.-J. Chem. Commun. 2012, 48, 7238-7240. 218 Sibi, M. P.; Liu, M. Org. Lett. 2001, 3, 4181–4184. 219 Enders, D.; Göddertz, D. P.; Beceño, C.; Raabe, G. Adv. Synth. Catal. 2010, 352, 2863– 2868. 220 Xu, D.-Q.; Wang, Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chem. Eur. J. 2010, 16, 4177–4180.

146

Chapter 2

Background

catalyst, providing access to a variety of enantioenriched b-amino acid derivatives (Scheme 2.17.a). Their results also indicate that the pyrazole template plays a crucial role in providing H-bond acceptor sites for better organization and hence higher levels of selectivity in these organocatalytic reactions (Scheme 2.17.b). (a)

Thiourea (30 mol%) R1 ONH 2

O

N N

N

R

S N H

N

OR1 R

19-98% 67-98% ee

CF3

F 3C

H

N

C6H 5CF3, MS 4Å 0ºC or 25ºC R = alkyl, Ar, CO 2Et R1 = Ph 2CH, PhCH 2, TBDMS

O

N H

OH

CF3

(b)

S F 3C

N H

N H

O

O

N N

H O R H 2N R Si face approach

Scheme 2.17. Thiourea catalysed asymmetric intermolecular aza-Michael reaction.

In 2012 Wang published two complementary procedures involving organocatalytic asymmetric sulfa-Michael additions to N-acyl pyrazoles. In the first one,217d a variety of thiols reacted with the easily available trans-4,4,4trifluorocrotonamide

in

excellent

yields

and

good

to

excellent

enantioselectivities (Scheme 2.18.a). They also evaluated the role of the pyrazole motif and the electron-withdrawing CF3 group, revealing the importance of both of them especially for a higher stereocontrol. In the second,217e they developed a direct construction of highly substitutes and biologically active thiochromanes via a sulfa-Michael-aldol reaction of 2mercaptobenzaldehyde

with

various

a,b-unsaturated

N-acyl

pyrazoles,

obtaining excellent diastereoselectivities and enantioselectivities for both b-aryl and b-alkyl conjugated substrates (Scheme 2.18.b).

147

Chapter 2

Background O

(a) F 3C

N

N

SR

Thiourea (5 mol%) + RSH

F 3C

Toluene, r.t., 20:1 Baylis-Hillman

Chapter 3

Objectives

3.2. Objectives Considering the aforementioned significance of sultams as privileged structures, it seemed an attractive and very appealing strategy to combine the previously studied organocatalytic intramolecular aza-Michael reaction (IMAMR) with a second intramolecular Michael addition, to eventually prepare a new family of bicyclic sultams. Thus, the key of this sequence rely on the use of vinyl sulfonamides as both, nitrogen nucleophiles and Michael acceptors. The preparation of the starting materials would involve a selective crossmetathesis (CM) reaction with the terminal olefin. Next, the conditions for the enantioselective IMAMR needed to be set to create the C-N bond. Finally, the sulfonamide moiety properly functionalised to act as the Michael acceptor would allow the following diastereoselective intramolecular Michael reaction (IMMR) generating a new C-C bond and affording bicyclic sultams with two new stereocenters (Scheme 3.10). Both the step-wise and the domino approaches will be evaluated. O O O S N H

Chiral Organocatalyst Enantioselective IMAMR C-N bond

R2 R1 [Ru] Catalyst

O N H

CM

O R1

O O S N * R1

O S

O

(acid or base) Diastereoselective IMMR C-C bond

O O S N * R1

* O

Scheme 3.10. Initial goal of the present chapter.

The sought molecules imply a very exclusive family of enantioenriched sultams, given the bridgehead position of the sulfonamide nitrogen, not reported to date in enantiomerically enriched manner.

243

Chapter 3

Results and Discussion

3.3. Results and Discussion Taking into account the previously introduced objectives, the selected results show the synthetic strategy for the desired highly functionalized starting materials, followed by the optimization of the first cyclisation (IMAMR) and then the different approaches for the final preparation of the targeted bicyclic sultams. 3.3.1. PREPARATION OF THE STARTING MATERIALS The starting materials of choice were vinyl sulfonamides 140 bearing a conjugated ketone in a remote position, in turn prepared by means of a CM reaction of starting sulfonamides 139 containing the terminal olefin moiety. Conjugated ketones were selected as Michael acceptors for the first cyclization step. Thus, using the methodology developed in the first chapter, the initial IMAMR will be evaluated. On the other hand, vinyl sulfonamides were the Michael acceptors of the second cyclization step, due to more simple access to those derivatives. Furthermore, the incorporation of substitution at the b-position of the starting vinyl sulfone would form an additional chiral center, increasing the complexity of the overall process. The synthesis of vinyl sulfonamides 140 is depicted below in Scheme 3.11. O O O S N H 139

R2 R1 [Ru] Catalyst CM

O N H

O S

O R1

140 R1 = alkyl

Scheme 3.11. Synthesis of starting material 140.

3.3.1.1. Synthesis of the conjugated sulfonamide-olefin 139 The synthesis of 139 started with nitrile 8. Its preparation was performed by initial reduction of the nitrile functionality to the primary amine by means of lithium aluminium hydride. Then, amine 9 was treated, without further purification, with 2-chloroethane-1-sulfonyl chloride, and the corresponding sulfonamide underwent elimination of HCl under the basic reaction conditions, 245

Chapter 3

Results and Discussion

generating the vinyl sulfone. Thus, the desired conjugated sulfonamide was finally obtained in a 3-step protocol in good yield (Scheme 3.12).

LiAlH 4, Et 2O

CN

Cl

NH 2

O O S Cl 138

O O S N H

Et 3N, DCM, r.t.

Δ 2h 9

8

139 46%

Scheme 3.12. Preparation of vinyl sulfonamide 139.

3.3.1.2. Selective

cross-metathesis

reaction:

Synthesis

a,b-

of

unsaturated sulfonamide-ketones 140. Once prepared starting sulfonamide 139, it was subjected to a crossmetathesis (CM) reaction with various vinyl ketones with the aim of obtaining the corresponding a,b-unsaturated substrates 140 for the subsequent conjugate additions (Figure 3.11). O N H

O S

O N H

O

O S

O N H

O

O S

O N H

O

O S

O Ph

140a

140c

140b

140d

Figure 3.11. Starting materials for the synthesis of bicyclic sultams.

Given the presence of two different terminal double bonds in substrate 139, regioselectivity problems would arise in the CM reaction. Additionally, a competitive ring closing metathesis reaction would also occur. Therefore, three possible scenarios have to be considered: the desired CM with the isolated olefin (Figure 3.12.a), a CM reaction with the vinyl sulfonamide (Figure 3.12.b) and a ring-closing-metathesis (RCM) cyclisation (Figure 3.12.c). O N H

O S

O O S N H

O

R1 O

R1 (a)

O HN S O

(b)

(c)

Figure 3.12. Plausible metathesis reactions with substrates 139.

246

Chapter 3

Results and Discussion

Based on electronic considerations, Grubbs

277

has developed a

classification of olefins in four different types according to their ability to undergo CM reactions.152 Using this data, is possible to make some predictions regarding the most favoured CM pair, as well as the propensity of the involved olefins to suffer homodimerization. A general trend could be extracted from this study; when the two olefins have a greater difference, which means that they belong to more separated olefin types, more favourable will be a CM reaction between them. Preparation of compounds 140 involved a CM reaction between olefin 139 and alkyl- or aryl-vinyl ketones 34. According to the previously mentioned classification, compound 139 contain two types of olefins; the vinyl sulfonamide is a type III olefin whereas the isolated olefin can be considered as a type I olefin. On the other hand, conjugated ketones 34a-c are olefins of type II whereas 34d, that bears substitution at the b-position, is a type III olefin. The most reactive olefin in CM reactions is the isolated one of compound 139; this type I olefin would react in a more favourable manner with conjugated ketones of type II (or type III). Olefins of type I have a high homodimerization ratio, but this could be avoided by adding a big excess of the conjugated ketone (usually 3 equivalents). Vinyl sulfonamides (olefins of type III) are low reactive olefins in CM reactions, which means that in the reaction of 139 and 34 it can be achieved a regioselective process to access the desired conjugated ketones 140 (Figure 3.13). The RCM reaction could be also a competitive reaction. Compound 139 would undergo RCM rendering an 8-membered ring sultam. Although those intramolecular

processes

are

more

favourable

entropically

than

the

intermolecular CM reaction, in this case the slow rate of formation of an 8membered ring and the use of diluted reactions would allow us to direct the process to the CM product.

277

Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140 and references therein. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am. Chem. Soc. 2003, 125, 11360–11370. 152

247

Chapter 3

Results and Discussion

O O Type III S N H

O

O

R1 Type II 34a-c

Type I 139

Ph Type III 34d

Figure 3.13. Classification of the involved olefins in 139 and 34.

Taking into account what has been exposed in the first chapter with regard to CM catalysts, it was chosen Hoveyda-Grubbs 2nd generation catalyst in DCM as solvent to optimize the desired transformation employing substrate 139 (Table 3.1). At room temperature the reaction did not progress satisfactorily (28% yield) (Table 3.1, entry 1) and at reflux the RCM product was observed as the major product (Table 3.1, entry 2). The increase of the catalyst loading (added in two times) was traduced in a slight improvement of the desired product until 40% (Table 3.1, entry 3). This result was improved by adding a 20 mol% of a Lewis acid (titanium isopropoxide) which coordinates the ketone oxygen making the enone more reactive for the CM reaction (Table 3.1, entry 4). Finally, the best results (86% yield) were obtained with a total load of 24 mol% of HG-II and seven equivalents of the conjugated ketone distributed into three separate additions (Table 3.1, entry 5). Table 3.1. Optimization of the regioselective CM reaction O O S N H

HG-II additive

O

+

DCM (0.3M) T

139

34a

O N H

O S

O

140a

Entry

HG-II (mol%)

additive

T (ºC)

Yield (%)a

1

8

-

25

28

2

8

-

45

RCMb

3

16

-

4 5 a

16 24

25

40

Ti(iPrO)4

c

25

53

Ti(iPrO)4

c

25

86

Isolated yields after flash chromatography purification. Ring-closing-metathesis product mainly obtained c 20 mol% loading b

248

Chapter 3

Results and Discussion

Then the optimized reaction conditions were applied to the synthesis of the different a,b-unsaturated sulfonamide-ketones 140 (Table 3.2). Compounds 140a-c (Table 3.2, entries 1-3) were obtained with good yields. However, synthesis of 140e wasn’t very efficient (Table 3.2, entry 4) due to the aforementioned problematic selectivity and also because of the steric sensitivity of the CM reaction, the methyl group at the R2 position would make the transformation rate slower, occurring in this way some side reactions such as the RCM and the formation of the Z-isomer (10% yield). Table 3.2. Synthesis of the conjugated sulfonamide-ketones 140 O O S N H

+

HG-II (3x8 mol%) Ti(iPrO) 4 (20 mol%)

O R2

139

R1

DCM (0.3M) r.t. 24h

34

O N H

O S

O R1

140

Entry

ketone

R1

R2

Product

Yield (%)a

1

34a

Me

H

140a

86

2

34b

Pr

H

140b

81

3

34c

Pent

H

140c

66

4

34d

Ph

Me

140d

31

a

Isolated yields after flash chromatography purification

3.3.2. ENANTIOSELECTIVE INTRAMOLECULAR AZA-MICHAEL REACTION OF a,b-UNSATURATED SULFONAMIDE-KETONES 140 278

With starting a,b-unsaturated ketones 140 in hand, next step was the optimization of the IMAMR conditions, taking as starting point the study disclosed in the first chapter172 and sulfonamide 140a as a model substrate. Thus, hydroquinidine primary amine (HQNH2) was chosen as organocatalyst and trifluoroacetic acid (TFA) as additive, evaluating different solvents and temperatures in order to find the best combination in terms of yield and enantioselectivity (Table 3.3). Equimolecular amounts of both catalyst and additive (20 mol%) in CHCl3 as solvent was firstly tested, yielding the Michael adduct 141a with quite good 172

Fustero, S.; del Pozo, C.; Mulet, C.; Lazaro, R.; Sánchez-Roselló, M. Chem. Eur. J. 2011, 17, 14267–14272.

249

Chapter 3

Results and Discussion

efficiency and enantiocontrol (Table 3.3, entry 1) after 24 hours of reaction at room temperature. Variation of the solvent to tetrahydrofuran gave slightly worse results, giving rise to 141a with only 47% yield and 82:18 er (Table 3.3, entry 2). Diminishing the reaction temperature to 0 ºC, enantioselectivities were improved, although yields were poor and incomplete conversion was achieved even after 5 days (Table 3.3, entries 3 and 4). Likewise, when the reaction was performed under microwave heating neither the yield nor the enantioenrichment of the product were improved (Table 3.3, entry 5). The employment of a highly polar solvent like acetonitrile did not allow the reaction to happen (Table 3.3, entry 6). A modification of the catalyst: additive ratio from 1:1 to 2:1 implied a drastic drop both in the yield and the enantiomeric relation in CHCl3 or THF as solvents (Table 3.3, entries 7 and 8). By decreasing the loadings, it was maintained enantioselectivity with slightly lower yield (Table 3.3, entries 9-10). The use of cyclopentyl methyl ether (CPME) as solvent, inspired by the good results obtained in the second chapter,67 did not lead to a higher enantiocontrol but the results were also good (Table 3.3, entry 11). Finally, a serendipitous miscalculation made us realize that a 1:2 combination of catalyst: additive of 13 and 26 mol% loadings, respectively, conduct to the best enantioselection (Table 3.3, entry 12). Other catalysts such as a squaramide and a BINOL phosphoric acid were also tested without any success.279 Table 3.3. Optimization of the IMAMR with conjugated sulfonamide-ketone 140a. OMe NH 2

N O N H

O S

H

N

HQNH 2, TFA

O

Solvent, T, t.

R1

R1 141a

140a

67

O O S N

Entry

HQNH2 (mol%)

TFA (mol%)

T (⁰C)

1

20

20

25

24

2

20

20

25

3

20

20

0

t (h) Solvent

O

Yield (%)

er

CHCl3

57

92:8

24

THF

47

82:18

120

CHCl3

22a

95:5

Sánchez-Roselló, M.; Mulet, C.; Guerola, M.; del Pozo, C.; Fustero, S. Chem. Eur. J. 2014, 20, 15697–15701.

250

Chapter 3

a b

Results and Discussion

4

20

20

0

120

THF

50a

94:6

5

20

20

100b

10

CHCl3

55

87:13

6

20

20

25

120

CH3CN

-

-

7

20

10

25

72

CHCl3

25

60:40

8

20

10

25

72

THF

13

55:45

9

15

15

25

22

CHCl3

58

95.5:4.5

10

10

10

25

24

CHCl3

40

96:4

11

11

11

25

13

CPME

85

96:4

12

13

26

25

17

CHCl3

76

97:3

Incomplete conversion after 5 days of reaction Microwave irradiation

The optimal IMAMR conditions (Table 3.3, entry 13) were extended to the rest of the prepared starting materials 140 to obtain a small library of enantioenriched N-heterocycles (Figure 3.3) with very good yields and excellent enantioselectivities in the synthesis of piperidines 141a-d. The assignment of the absolute configuration of the newly created stereocenter has been determined to be R in consistence with the previously described methodology for the organocatalytic IMAMR of conjugated ketones with HQNH2, which extension to the present transformation seems reasonable (Scheme 1.42). Furthermore, it was later confirmed by an X-ray analysis of a crystalline sultam (Figure 3.6). O O S N

O 141a 76% 97:3 er

O O S N

O 141b 71% 98.5:1.5 er

O O S N

O 141c 90% 98:2 er

O O S N

O Ph 141d 85% 97.5:2.5 er

Figure 3.3. Scope of the IMAMR of a,b-unsaturated sulfonamide-ketones 140.

It is important to point out here that to date, it was not possible to perform both cyclisations in a domino manner. All the attempts mentioned in Table 3 indicated that the process stop after the IMAMR. That means that the synthesis of the desired bicyclic lactams has to be performed in a step-wise fashion.

251

Chapter 3

Results and Discussion

3.3.3. DIASTEREOSELECTIVE INTRAMOLECULAR MICHAEL REACTION OF NHETEROCYCLIC a,b-UNSATURATED SULFONAMIDES 141 With the chiral N-heterocycles 141 in hand, the last step of the present study was to develop a diastereoselective IMMR to synthesize the desired enantioenriched sultams 142. Initially, it was performed the synthesis of final products in a racemic manner. To this end, it was envisioned the possibility of performing both cyclisations in a domino fashion, under basic catalysis. To our delight, when compounds 140 were treated with NaH, the domino protocol took place in a very efficient way in only 4-6 h, giving rise to the bicyclic sultams 142 in good yields and complete diastereoselectivity (Scheme 3.13). O O S N O H

O O S N

NaH

*

THF/DMF (5:1) 0.03 M, 25 ºC

R1

*

R1 O 142 70-87%

140 1 R = alkyl

Scheme 3.13. Synthesis of the racemic bicyclic sultams 142.

With this result, the next step was the preparation of sultams 142 in a enantiomerically enriched manner. Since it was not possible to perform the organocatalytic process in a tandem fashion, piperidines 141 were subjected to the intramolecular Michael addition in basic media. Again, the application of the conditions developed for the racemic synthesis was very effective, giving rise to the final sultams 142 in good yields with sodium hydride in THF/DMF (Figure 3.4). O O S N

O O S N

O O S N

O O S N

*

*

*

*

*

*

O 70% 142a

O 81% 142b

* O

81% 142c

*

Ph

O

87% 142d

Figure 3.4. Desired bicyclic sultams 142.

Nevertheless, the chirality of the sultams could not be determined by the HPLC used until the moment, since it has a UV-detector and any of the final

252

Chapter 3

Results and Discussion

products (except sultam 145d that contains an aromatic ring) were able to significantly absorb UV light. It was attempted the alternative procedure for the determination of the enantioselectivity used in the second chapter, consisting on the formation of diastereoisomers with a europium salt in order to unfold any of the 1H-NMR signals. However, their spectra were quite complex and any of the signals reacted in the aimed way. Finally, an alternative HPLC apparatus, with a refractive index detector (RID) instead of the UV one led us to determine the final enantiomeric excesses. To our disenchantment, all of the synthesized sultams (step-wise and one-pot prepared) resulted to be racemic. Apparently, a retro-aza-Michael reaction was taking place with the use of NaH (Scheme 3.14), epimerizing in this way the chiral stereocenter initially created with aid of the organocatalyst. O O S N H H R1 O 141

H N

COR1 S O2

O O S N O H

NaH R1

NaH 140

O O S N

R1 O (±)-142

Scheme 3.14. Base-mediated retro-aza-Michael reaction and racemic synthesis of 142.

With a proper methodology to examine sultams chirality in hand, it was developed a thoroughly study to discover the IMMR conditions that could avoid the undesired retro-aza-Michael reaction (Table 3.4). A variety of bases, acids and organocatalysts (Table 3.4, entries 1-18) were tested unsuccessfully until a slight chirality maintenance was finally achieved (22% ee) with the use of a Verkade’s base (Table 3.4, entry 19). However, by modifying the reaction conditions it could not be accomplished a good combination of yield and enantiocontrol with any Verkade’s base (Table 3.4, entries 20-23). Was the use of phosphazene base P2-Et, included in superbases family, 280 which finally came up with an acceptable rate of chirality and yield of the bicyclic sultam (Table 3.4, entry 24). The change of the solvent from THF to toluene did not allowed the reaction to be completed (Table 3.4, entry 25). And by reducing the loading of the base to 10 mol% there was any further improvement in the chirality maintenance and a longer reaction time was needed for a slightly lower 280

Schlosser, M. Pure Appl. Chem. 1988, 60, 1627–1634.

253

Chapter 3

Results and Discussion

yield (Table 3.4, entry 26). The employment of a bulkier phosphazene superbase, seeking a better stereocontrol, resulted to be too hindered to allow the reaction to proceed (Table 3.4, entry 27). Table 3.4. Optimization of the IMMR of N-heterocyclic conjugated sulfonamides 144. O O S N

O O S N

Reactants

*

Solvent, T R1 141

N

P N N N

iPr-Verkade's base

N

*

R1

O

O

142

P N N

N iBu-Verkade's base

N N P N

N

N P N N

N N P N

Phosphazene base P 2-Et

N

N P N N

Phosphazene base P 2-tBu

Entry

Reactants

Solvent

T (ºC)

Results

1

LiHMDS

THF

-78/0/25/67

SM

2

KHMDS

THF

25

Decomp.

3

tBuOK

THF

25a

Racemic prod.

4

BF3OEt2

THF

25

SM

5

BF3OEt2

DCM

60-80b

SM

6

TBAF

THF

25

SM

7

THF

25

SM

MeOH

25

SM

DCM

45

SM

Et2O

0 to 25

Side product

MEOH

25

Side product

DCM

45

Side product

13

DBU Thiourea+ L-arginine Thiourea+trans-2,5dimethylpiperazine CF3SO3TMS+Et3N +BF3OEt2 trans-2,5-dimethyl piperazine trans-2,5-dimethyl piperazine Pyrrolidine

MeOH

25/65

Side product

14

L-proline

MeOH

25

Side product

15

L-proline

DMF

25

Side product

THF

67

8 9 10 11 12

16 17 18

254

BEMP

c

BEMP

c

BEMP

c

THF THF

Racemic prod.

70-120 160

b

b

Racemic prod. Side product.

Chapter 3

Results and Discussion

19

iPr-Verkade’s based

THF

25

93%, 22% ee

20

iPr-Verkade’s based

THF

-78 to -40

95%, 50% ee

21

iPr-Verkade’s based

THF

-40e

78%, 22% ee

22

iPr-Verkade’s based

THF

-78e,f

24%, 95% eeh

23

iBu-Verkade’s baseg

THF

-78e

SM

24

Phosphazene base P2-Eti

THF

-78e,j

77%, 84% eeh

25

Phosphazene base P2-Eti

Toluene

-78e

33% (50%conv.)

26

Phosphazene base P2-Eti

THF

-78e,k

70%, 88% eel

27

Phosphazene base P2-tBum

THF

-78e,j

SM

a

20 minutes Microwave irradiation c 2-tert-Butylimino-2-diethyl amino-1,3-dimethylperhydro-1,3,2-diazaphosphorine d 2,8,9-Triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane e MS 4Å, vial heated with microwave irradiation at 120ºC for 10 minutes f 26 hours g 2,8,9-Triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane h SM: 141a (95% ee) i 1-Ethyl-2,2,4,4,4-pentakis(dimethyl amino)-2λ5,4λ5-catenadi(phosphazene) j 1 equiv. base, 2 hours k 0,1 equiv. base, 24 hours l SM: 141b (97% ee) m 1-tert-Butyl-2,2,4,4,4-pentakis(dimethyl amino)-2λ5,4λ5-catenadi(phosphazene) b

Then, according to entry 24, the use of 1 equivalent of the phosphazene base P2-Et in THF during 2 hours of reaction at -78ºC chosen as the optimal condition for the IMMR, were applied for the synthesis of the five bicyclic sultams 142 (Figure 3.5). They were all obtained with good yields and moderate to good enantiomeric excesses, with a slight erosion of the chirality from that of the starting piperidines 141 (Figure 3.3). Conversely, the diastereoselectivity of the second cycloaddition was complete (>99% d.r.) as it could be checked in the more sensitive UVD-HPLC of the aromatic sultam 142d as well as in the NMR spectra, where just one diastereoisomer was observed. O O S N

O O S N

O 142a 77% 93:7 er

O O S N

O 142b 70% 94:6 er

O 142c 73% 95:5 er

O O S N

Ph

O

142d 80% 90:10 er

Figure 3.5. Scope of chiral bicyclic sultams 142.

255

Chapter 3

Results and Discussion

The absolute configuration of the final products was determined by XRay analysis of crystals of sultam 142a, possible given the solid consistence of these sultams. Thus, it was confirmed the anti-configuration of the two stereocenters as (C14S, C14aR) according to the structure shown in Figure 3.6, as well as the expected R configuration of the first-created stereocenter. The same stereochemical evolution was assumed of all sultams 142.

Figure 3.6. X-Ray of sultam 142a.

3.3.4. COMPLEMENTARY ONGOING WORK Two complementary studies related to the project showed in the present chapter have been initiated. The first one is the extension of the scope of the process to 5-membered rings and to benzofused derivatives (Scheme 3.15.a). The second one, as a consequence of the problems encountered in the second cyclization step, involve the modification of this synthetic sequence to access a different family of bicyclic sultams (Scheme 3.15.b).

256

Chapter 3

(a) (

Results and Discussion

O O S N

)m

(b)

( )n R O O S N

R

O 142

(

O

)m

N H

O S

O O ( )m S N

O

( )n

( )n

R

R

143

140 n,m = 0,1,2

O Scheme 3.15. Complementary work within the sultams project.

The extension of the scope to benzofused derivatives is currently ongoing, and some problems related with the preparation of the starting materials have to be solved. Regarding the synthesis of sultams containing a five membered ring, the initial studies indicated that the IMAMR takes place with low levels of stereocontrol. Additionally, the use of the phosphazene base P2-Et does not avoid the racemization of the final products. The synthesis of the second family of sultams 143, was designed involving a Wittig reaction over the ketone moiety of substrates 141, followed by a RCM reaction with the vinyl sulfonamide. An initial attempt was performed in substrate 141a, which was subjected to the corresponding Wittig reagent. Unfortunately, the phosphorus ylide acted as a base and the racemization of the starting material was produced (Scheme 3.16). O O S N

R 141

O

BrPPh 3CH3 NaHMDS THF, 0 ºC to r.t. 12 h

O O S N

R1 O (±)-142

Scheme 3.16. Attempt of Wittig reaction to access sultams 143.

To overcome this problem, a methylenation reaction that avoid basic media was performed. In this context, it was described in the literature that Petasis reagent could act as an efficient methylenating agent without the need

257

Chapter 3

Results and Discussion

of a base. 281 Therefore, when compound 141a was treated with Cp2TiMe2 (Petasis reagent) in toluene at reflux for 20 hours, the methylenation of the ketone was produced efficiently. With the dienic compound 144 in hand, the RCM reaction was carried out with second generation Hoveyda-Grubbs catalyst (HG-II), affording the desired sultam 143 in good yield. An HPLC analysis showed that the integrity of the chiral center was maintained in this sequence, and bicyclic sultam 143a was obtained with a small erosion of the final ee (Scheme 3.17). The extension of this methodology to the rest of starting ketones 141 is currently underway in our laboratory. O O S N * O 141a

Cp 2TiMe2 Toluene Δ 20 h

O O S N *

144a 75%

HG-II (20 mol%) Toluene Δ 24 h

O O S N * 143a 71% 92:8 er

Scheme 3.17. Alternative route from piperidines 141 for the synthesis of sultams 143.

281

a) Petasis N. A., Bzowej E. I., J. Am. Chem. Soc. 1990, 112, 6392–6394. b) Tetrahedron Letters 1995, 36, 2393-2396. c) Adriaenssens L. V., Hartley R. C., J. Org. Chem. 2007, 72, 10287–10290.

258

Chapter 3

Conclusions

3.4. Conclusions A step-wise procedure for the synthesis of enantiomerically enriched bicyclic sultams has been performed. It is started with an enantioselective intramolecular aza-Michael reaction of a sulfonamide nucleophile to an a,bunsaturated ketone by means of a catalytic system composed by a molecule of 9-amino-9-deoxy-epi-hydroquinidine

organocatalyst

molecules

Followed

of

trifluoroacetic

acid.

by

(HQNH2) a

and

two

superbase-mediated

diastereoselective intramolecular Michael reaction of the a-carbonylic carbon to the conjugated sulfonamide. This methodology is a nice combination of the two studies performed in the previous chapters and allows the access to an especial family of sultams with the nitrogen in the bridgehead position of the bicycle, structures not reported to date.

259

Chapter 3

Experimental Section

3.5. Experimental Section X-RAY DETERMINATION X-ray diffraction analysis of compound 142a was performed with an automatic four cycles diffractometer with Kappa geometry: KappaCCD (nonius). This apparatus held an Oxford low temperature system and an informatics platform for the control, processing and resolution of the crystalline structures. DETERMINATION OF THE ENANTIOMERIC RATIO All the aliphatic sultams were analysed with an HPLC Agilent 1100 series equipped with a refractive index detector (RID). 3.5.1. PREPARATION OF FUNCTIONALISED SULFONAMIDES 142

CN

1) LiAlH 4, Et 2O Δ 2h 2) Et 3N, DCM

8

Cl

O O S Cl

O O S N H 139

To a suspension of LiAlH4 (6 mmol) in diethyl ether (10 mL) was added dropwise nitrile 8 (2,0 mmol) at room temperature. After heating for 2h at reflux, the suspension was allowed to reach room temperature and Na2SO4·10H2O was added with vigorous stirring until aluminium salts turned white. The suspension was filtered through a short pad of Celite® washing with small portions of diethyl ether. The filtrate was concentrated under vacuum obtaining a yellow oil that used without further purification. The crude amine was dissolved in CH2Cl2 (4 mL) and triethyl amine (2.0 equiv.) was added at 0 ºC followed by 2-chloroethane-1-sulfonyl chloride (1.0 equiv.). The reaction mixture was allowed to reach room temperature overnight and then it was hydrolised with HCl (3 molar), extracted with CH2Cl2 and dried over Na2SO4 anhydrous. Finally, solvents were removed and the crude mixture purified by flash chromatography with hexanes: ethyl acetate as eluents.

261

Chapter 3

Experimental Section

N-(5-hexenyl)ethenesulfonamide (139) O O S N H

1

Physical state:

Pale yellow oil

Empiric Formula:

C8H15NO2S

Molecular weight (g/mol):

189.27

Yield (%):

46

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

6.50 (dd, J = 16.6, 9.9 Hz, 1H), 6.19 (dd, J = 16.6, 0.7 Hz, 1H), 5.91 (dd, J = 9.9, 0.4 Hz, 1H), 5.84 – 5.65 (m, 1H), 4.94 (tdd, J = 10.2, 1.9, 1.1 Hz, 3H), 2.97 (dd, J = 13.4, 6.6 Hz, 2H), 2.02 (t, J = 7.1 Hz, 2H), 1.60 – 1.47 (m, 2H), 1.47 – 1.34 (m, 2H) 138.6, 136.3, 126.9, 115.3, 43.3, 33.5, 29.6, 26.1

HRMS (EI+):

Calcd. for C8H15NO2S [M+]: 190.0896, found: 190,0890

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 5:1 as eluent.

3.5.2. SYNTHESIS OF N-CONJUGATED SULFONAMIDE a,b-UNSATURATED KETOAMINES 140 O O S N H 139

+

HG-II (24 mol%)

O R2

R1 34

Ti(iPrO) 4 (20 mol%) DCM, r.t., 24 h

O N H

O S

Mes O R1

140a-d

N N

Mes

Cl Ru Cl O iPr HG-II

To a solution of N-protected amine 139 (1.0 equiv.) in CH2Cl2 (0.3 M) under nitrogen atmosphere, the corresponding conjugated ketone 34 (3.0 equiv.), titanium isopropoxide (20 mol%) and an initial 8 mol% charge of Hoveyda-Grubbs 2nd generation catalyst were added. Two more portions of catalyst (24 mol% total) were added together with 2.0 more equivalents of ketone, after 2-3 hours stirring the crude at room temperature. The resulting solution was overall stirred for 12 h at room temperature and then solvents were removed and the crude mixture purified by flash chromatography with hexanes: ethyl acetate as eluents.

262

Chapter 3

Experimental Section

(E)-N-(7-oxo-5-octenyl)ethenesulfonamide (140a)

O N H

1

O S

O

Physical state:

Brown oil

Empiric Formula:

C10H17NO3S

Molecular weight (g/mol):

231.31

Yield (%):

86

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

6.76 (dt, J = 15.9, 6.9 Hz, 1H), 6.50 (dd, J = 16.5, 9.8 Hz, 1H), 6.23 (d, J = 16.6 Hz, 1H), 6.07 (dt, J = 15.9, 1.4 Hz, 1H), 5.94 (dd, J = 9.9, 3.9 Hz, 1H), 4.58 (s, 1H), 3.10 – 2.92 (m, 2H), 2.34 – 2.15 (m, 5H), 1.65 – 1.45 (m, 4H)

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

198.9, 147.8, 135.9, 131.5, 126.4, 42.6, 31.7, 29.2, 26.8, 24.9

HRMS (EI+):

Calcd. for C10H17NO3S [M+]: 232,1002, found: 232,1005

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 1:1 as eluent.

(E)-N-(7-oxo-5-decenyl)ethenesulfonamide (140b)

O N H

O S

O

Physical state:

Brown oil

Empiric Formula:

C12H21NO3S

Molecular weight (g/mol):

259.36

Yield (%):

81

1

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

6.75 (dt, J = 15.9, 6.9, 1H), 6.47 (dd, J = 16.6, 9.9, 1H), 6.17 (d, J = 16.6, 1H), 6.05 (dt, J = 15.9, 1.5, 1H), 5.90 (d, J = 9.9, 1H), 4.98 (t, J=5.9, 1H), 2.97 (q, J=6.5, 2H), 2.46 (t, J=7.3, 2H), 2.19 (td, J=6.9, 5.8, 2H), 1.67 – 1.41 (m, 6H), 0.88 (t, J=7.4, 3H) 201.0, 146.4, 135.9, 130.7, 126.6, 42.7, 42.1, 31.8, 29.3, 25.0, 17.7, 13.8

HRMS (EI+):

Calcd. for C12H21NO3S [M+]: 260,1315, found: 260,1308

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 1:1 as eluent.

263

Chapter 3

Experimental Section

(E)-N-(7-oxo-5-dodecenyl)ethenesulfonamide (140c) O O S N O H

Physical state:

Brown oil

Empiric Formula:

C14H25NO3S

Molecular weight (g/mol):

287.42

Yield (%):

66

1

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

6.42 (dd, J = 16.5, 9.7, 1H), 6.20 (d, J = 16.5, 1H), 5.88 (d, J = 9.7, 1H), 4.50 – 4.31 (m, 1H), 3.63 (d, J = 12.8, 1H), 3.04 – 2.91 (m, 1H), 2.81 – 2.74 (m, 2H), 1.74 – 1.45 (m, 8H), 1.38 – 1.16 (m, 4H), 0.89 (t, J = 7.0, 3H)

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

208.6, 136.4, 126.1, 49.0, 43.3, 41.2, 31.5, 28.7, 25.5, 25.4, 23.5, 22.6, 18.8, 14.0

HRMS (EI+):

Calcd. for C14H25NO3S [M+]: 288,4255, found: 288,1625

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 1:1 as eluent.

(E)-N-(7-oxo-7-phenyl-5-heptenyl)ethenesulfonamide (140d) O O S N O H Ph

Physical state:

Brown oil

Empiric Formula:

C15H19NO3S

Molecular weight (g/mol):

293.38

Yield (%):

35

1

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

8.01 – 7.86 (m, 2H), 7.59 – 7.50 (m, 1H), 7.49 – 7.41 (m, 2H), 7.00 (dd, J = 14.3, 7.6, 1H), 6.88 (d, J = 15.4, 1H), 6.50 (dd, J = 16.5, 9.9, 1H), 6.22 (d, J = 16.5, 1H), 5.92 (d, J = 9.8, 1H), 4.73 (s, 1H), 3.02 (t, J = 6.2, 3H), 2.43 – 2.22 (m, 2H), 1.59 (dd, J = 8.3, 5.1, 4H) 190.9, 148.9, 137.9, 136.0, 132.9, 128.7, 128.4 126.7, 126.4, 42.8, 32.2, 29.5, 25.2

HRMS (EI+):

Calcd. for C15H19NO3S [M+]: 294,3885, found: 294,1157

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 1:1 as eluent.

264

Chapter 3

Experimental Section

3.5.3. AZA-MICHAEL ADDUCT SYNTHESIS: PREPARATION OF 2-SUBSTITUTED NITROGEN HETEROCYCLES 141 O N H

O S

O O S N

13 mol% HQNH 2 26 mol% TFA

O

140a-d

NH 2

N

CHCl3, r.t., 12h .

R1

OMe

H R1

O

141a-d

N

HQNH 2

In a 25 mL round bottomed flask, a,b-unsaturated ketones 140a-d (1.0 equiv.) were dissolved in chloroform (0.1 M). A mixture of catalyst HQNH2 (13 mol%) and trifluoroacetic acid (TFA) (26 mol%, added from a freshly prepared stock solution in chloroform) was added and the resulting solution was stirred at room temperature. After 24-96 hours, the crude reaction mixture was subjected to flash chromatography on silica gel using mixtures of hexanes: ethyl acetate as

eluents

to

afford

the

corresponding

N-heterocycles

141a-d.

The

enantiomeric ratios were determined by means of HPLC analysis with a Chiralpack AD column (25 cm x 0.46 cm). 1-(1-(vinylsulfonyl)piperidin-2-yl)-2-propanone (141a)

O O S N

O

1

Physical state:

Colorless oil

Empiric Formula:

C10H17NO3S

Molecular weight (g/mol):

231.31

Yield (%):

76

Enantiomeric relation:

97:3

Optical rotation [a]D25:

+20 (c 1.0, CHCl3)

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

HRMS (EI+):

6.50 – 6.35 (m, 1H), 6.20 (dd, J = 16.5, 0.5, 1H), 5.89 (dd, J = 9.7, 0.5, 1H), 4.42 (dd, J = 12.8, 5.5, 1H), 3.62 (d, J = 12.8, 1H), 2.98 (dd, J = 14.5, 11.6, 1H), 2.81 (d, J = 7.1, 2H), 2.23 – 2.11 (m, 3H), 1.79 – 1.43 (m, 7H) 206.1, 136.3, 126.2, 49.0, 44.7, 41.3, 30.4, 28.7, 25.3, 18.8

Calcd. for C10H17NO3S [M+]: 232.1002, found: 232,0996

265

Chapter 3 Remarks:

Experimental Section ê Reaction stirred during 17 hours. ê Purification by flash chromatography with hexanes: ethyl acetate 2:1 as eluent. ê The er value was determined by HPLC analysis using a Chiralpack AD column (hexane: isopropanol 90:10); flow rate = 1.0 mL/min, tmajor=21.0 min, tminor=18.9 min

1-(1-(vinylsulfonyl)piperidin-2-yl)-2-pentanone (141b)

O O S N

O

1

Physical state:

Yellow oil

Empiric Formula:

C12H21NO3S

Molecular weight (g/mol):

259.36

Yield (%):

71

Enantiomeric relation:

98.5:1.5

Optical rotation [a]D25:

-10 (c 1.0, CHCl3)

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

6.43 (dd, J = 16.5, 9.7, 1H), 6.20 (d, J = 16.5, 1H), 5.88 (d, J = 9.7, 1H), 4.42 (dd, J = 12.2, 5.8, 1H), 3.63 (d, J = 13.0, 1H), 3.03 – 2.91 (m, 1H), 2.85 – 2.70 (m, 2H), 2.42 (t, J = 7.3, 2H), 1.76 – 1.43 (m, 8H), 0.91 (t, J = 7.4, 3H) 208.5, 136.4, 126.1, 49.0, 45.7, 43.7, 41.2, 28.7, 25.4, 18.8, 17.3, 13.8

HRMS (EI+):

Calcd. for C12H21NO3S [M+]: 260,1315, found: 260,1310

Remarks:

ê Reaction stirred during 21 hours. ê Purification by flash chromatography with hexanes: ethyl acetate 2:1 as eluent. ê The er value was determined by HPLC analysis using a Chiralpack AD column (hexane: isopropanol 90:10); flow rate = 1.0 mL/min, tmajor=13.0 min, tminor=9.9 min

266

Chapter 3

Experimental Section

1-(1-(vinylsulfonyl)piperidin-2-yl)-2-heptanone (141c)

O O S N

O

1

Physical state:

Yellow oil

Empiric Formula:

C14H25NO3S

Molecular weight (g/mol):

287.42

Yield (%):

90

Enantiomeric relation:

98.5:2.5

Optical rotation [a]D25:

+1,5 (c 1.0, CHCl3)

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

6.42 (dd, J = 16.5, 9.7, 1H), 6.20 (d, J = 16.5, 1H), 5.88 (d, J = 9.7, 1H), 4.51 – 4.33 (m, 1H), 3.63 (d, J = 12.8, 1H), 3.05 – 2.89 (m, 1H), 2.82 – 2.74 (m, 2H), 2.47 – 2.38 (m, 2H), 1.78 – 1.45 (m, 8H), 1.39 – 1.16 (m, 4H), 0.89 (t, J = 7.0, 3H)

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

208.6, 136.4, 126.1, 49.0, 43.6, 43.3, 41.2, 31.5, 28.7, 25.5, 25.4, 23.5, 22.6, 18.8, 14.0

HRMS (EI+):

Calcd. for C14H25NO3S [M+]: 288,4255, found: 288,1625

Remarks:

ê Reaction stirred during 18 hours. ê Purification by flash chromatography with hexanes: ethyl acetate 2:1 as eluent. ê The er value was determined by HPLC analysis using a Chiralpack AD column (hexane: isopropanol 90:10); flow rate = 1.0 mL/min, tmajor=10.9 min, tminor=9.1 min

1-phenyl-2-(1-(vinylsulfonyl)piperidin-2-yl)-1-ethanone (141d)

O O S N

Ph

1

O

H-RMN (CDCl3, 300 MHz) δ (ppm):

Physical state:

Colorless oil

Empiric Formula:

C15H19NO3S

Molecular weight (g/mol):

287.42

Yield (%):

85

Enantiomeric relation:

97.5:2.5

Optical rotation [a]D25:

-1,2 (c 1.0, CHCl3)

8.06 – 7.90 (m, 2H), 7.63 – 7.54 (m, 1H), 7.54 – 7.43 (m, 2H), 6.43 (dd, J = 16.5, 9.7, 1H), 6.20 (d, J = 16.5, 1H), 5.85 (d, J = 9.7, 1H), 4.59 (dd, J = 10.6, 7.2, 1H), 3.78 – 3.64 (m, 1H), 3.48 – 3.27 (m, 2H), 3.16 – 3.01 (m, 1H), 1.87 – 1.41 (m, 6H)

267

Chapter 3 13

Experimental Section

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

197.7, 136.7, 136.3, 133.6, 128.9, 128.4, 126.1, 49.6, 41.3, 39.7, 28.3, 25.5, 18.8

HRMS (EI+):

Calcd. for C15H19NO3S [M+]: 294,3885, found: 294,1156

Remarks:

ê Reaction stirred during 144 hours. ê Purification by flash chromatography with hexanes: ethyl acetate 2:1 as eluent. ê The er value was determined by HPLC analysis using a Chiralpack AD column (hexane: isopropanol 90:10); flow rate = 1.0 mL/min, tmajor=29.7 min, tminor=16.2 min

3.5.4. MICHAEL ADDUCT SYNTHESIS: PREPARATION OF SULTAMS 142 O O S N

R1 141a-d

O

1eq. P 2-Et MS 4Å, THF -78ºC, 2h

O O S N

R1

N N N P N P N N N

O

142a-d

P 2-Et

A microwave oven-dried vial was filled with oven-dried MS 4Å and stirring bar and heated at 120ºC during 10 minutes under microwave irradiation. Then, piperidine 141a-d (1.0 equiv.) was dissolved in THF (0.1 M) and introduced into the vial. After immersing it in a -78ºC acetone bath, phosphazene base P2-Et was added and the resulting mixture was stirred at that temperature for 2 hours. Then the crude reaction mixture was hydrolysed with HCl 1M, extracted with AcOEt and dried over Na2SO4 anhydrous. Finally it was subjected to flash chromatography on silica gel using mixtures of hexanes: ethyl acetate as eluents to afford the corresponding bicyclic sultams 142a-e. The enantiomeric ratios were determined by means of RID- or UVD-HPLC analysis with a Chiracel OD-H column (25 cm x 0.46 cm).

268

Chapter 3

Experimental Section

1-((4S,4aR)-1,1-dioxidooctahydropyrido[1,2-b][1,2]thiazin-4-yl)-1-ethanone (142a)

O O S N

O

1

Physical state:

White solid

Empiric Formula:

C10H17NO3S

Molecular weight (g/mol):

231.31

Yield (%):

77

Melting point (ºC)

34-36

Enantiomeric relation:

93:7

Optical rotation [a]D25:

+1,9 (c 1.0, CHCl3)

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

3.78 (ddd, J = 10.5, 6.5, 4.0, 1H), 3.40 – 3.24 (m, 1H), 3.20 – 2.95 (m, 3H), 2.86 (ddd, J = 12.5, 10.9, 3.8, 1H), 2.44 – 2.25 (m, 1H), 2.25 – 2.10 (m, 4H), 1.83 – 1.19 (m, 9H)

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

208.1, 58.5, 50.0, 45.2, 42.1, 29.8, 29.5, 26.1, 24.7, 21.0

HRMS (EI+):

Calcd. for C10H17NO3S [M+]: 232,1002, found: 232,0996

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 1:1 as eluent. ê The er value was determined by RID-HPLC analysis using a Chiracel OD-H column (hexane: isopropanol 85:15); flow rate = 1.0 mL/min, tmajor= 23.2 min, tminor= 20.3 min

1-((4S,4aR)-1,1-dioxidooctahydropyrido[1,2-b][1,2]thiazin-4-yl)-1-butanone (142b)

O O S N

O

1

H-RMN (CDCl3, 300 MHz) δ (ppm):

Physical state:

White solid

Empiric Formula:

C12H21NO3S

Molecular weight (g/mol):

259.36

Yield (%):

70

Melting point (ºC):

193-195

Enantiomeric relation:

94:6

Optical rotation [a]D25:

(c 1.0, CHCl3)

3.72 (ddd, J = 10.7, 6.7, 4.0, 1H), 3.35 – 3.21 (m, 1H), 3.12 – 2.89 (m, 3H), 2.79 (ddd, J = 12.5, 10.8, 3.7, 1H), 2.51 – 2.19 (m, 3H), 2.05 (dq, J = 14.1, 3.8, 1H), 1.75 – 1.14 (m, 8H), 0.91 – 0.77 (m, 3H)

269

Chapter 3 13

Experimental Section

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

210.5, 58.9, 49.6, 45.6, 45.4, 42.3, 29.8, 26.5, 24.9, 21.4, 17.0, 14.1

HRMS (EI+):

Calcd. for C12H21NO3S [M+]: 260,1276 , found: 260,1312

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 1:1 as eluent. ê The er value was determined by RID-HPLC analysis using a Chiracel OD-H column (hexane: isopropanol 85:15); flow rate = 1.0 mL/min, tmajor=17.4 min, tminor=15.0 min

1-((4S,4aR)-1,1-dioxidooctahydropyrido[1,2-b][1,2]thiazin-4-yl)-1-hexanone (142c)

O O S N

O

1

Physical state:

White solid

Empiric Formula:

C12H21NO3S

Molecular weight (g/mol):

287.42

Yield (%):

73

Melting point (ºC):

>310ºC

Enantiomeric relation:

95:5

Optical rotation [a]D25:

(c 1.0, CHCl3)

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

3.79 (ddd, J = 10.6, 6.6, 3.9, 1H), 3.41 – 3.28 (m, 1H), 3.19 – 2.92 (m, 3H), 2.92 – 2.80 (m, 1H), 2.60 – 2.24 (m, 3H), 2.21 – 2.05 (m, 1H), 1.84 – 1.14 (m, 12H), 0.89 (dd, J=9.1, 4.8, 3H) 210.7, 58.9, 49.6, 45.6, 43.5, 42.3, 31.7, 29.8, 26.5, 24.9, 23.3, 22.8, 21.4, 14.3

HRMS (EI+):

Calcd. for C12H21NO3S [M+]: 288,1519, found: 288,1632

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 1:1 as eluent. ê The er value was determined by RID-HPLC analysis using a Chiracel OD-H column (hexane: isopropanol 85:15); flow rate = 1.0 mL/min, tmajor=15.2 min, tminor=13.3 min

270

Chapter 3

Experimental Section

1-((4S,4aR)-1,1-dioxidooctahydropyrido[1,2-b][1,2]thiazin-4yl)(phenyl)methanone (142d)

O O S N

Ph

1

O

Physical state:

White solid

Empiric Formula:

C15H19NO3S

Molecular weight (g/mol):

293.38

Yield (%):

80

Melting point (ºC):

105-108

Enantiomeric relation:

90:10

Optical rotation [a]D25:

(c 1.0, CHCl3)

H-RMN (CDCl3, 300 MHz) δ (ppm):

13

C-RMN (CDCl3, 75.5 MHz) δ (ppm):

8.00 – 7.93 (m, 2H), 7.67 – 7.60 (m, 1H), 7.56 – 7.48 (m, 2H), 3.97 (ddd, J = 10.7, 6.6, 3.8, 1H), 3.78 (ddd, J = 12.3, 10.4, 3.5, 1H), 3.54 – 3.43 (m, 1H), 3.22 – 3.12 (m, 2H), 3.13 – 3.01 (m, 1H), 2.49 (dddd, J = 14.2, 12.3, 10.4, 6.9, 1H), 2.28 – 2.14 (m, 1H), 1.87 – 1.44 (m, 6H) 200.3, 136.4, 134.1, 129.2, 128.4, 59.7, 45.8, 44.0, 42.1, 29.8, 27.2, 24.7, 21.6

HRMS (EI+):

Calcd. for C15H19NO3S [M+]: 294,3885, found: 294,1158

Remarks:

ê Purification by flash chromatography with hexanes: ethyl acetate 1:1 as eluent. ê The er value was determined by UVD-HPLC analysis using a Chiracel OD-H column (hexane: isopropanol 85:15); flow rate = 1.0 mL/min, tmajor=51.0 min, tminor=43.2 min

271

Chapter 3

Experimental Section

3.5.5. HPLC TRACES OF ENANTIOENRICHED COMPOUNDS 141 AND 142

SLL-09 rac 95.5 AD - CH14

O O S N

18,333 49,89

1000000

20,467 50,11

O

Intensity [µV]

(±)-141a

500000

0

Retention Time [min]

12,0

14,0

16,0

18,0

20,0

22,0

24,0

26,0

28,0

600000

CM-III-047 95.5 AD - CH14

21,120 97,17

O O S N

400000

Intensity [µV]

O (+)-141a 97:3 er 200000

0 18,880 2,83 Retention Time [min]

14,0

272

16,0

18,0

20,0

22,0

24,0

26,0

28,0

30,0

Chapter 3

Experimental Section

200000 SLL-041 90.10 AD - CH14

O O S N

9,693 49,81

12,720 50,19

O (±)-141b

Intensity [µV]

100000

0

Retention Time [min]

6,0

8,0

10,0

12,0

14,0

16,0

18,0

20,0

1000000 CM-III-105.1 90.10 AD - CH14

13,760 98,50

O O S N

O (-)-141b 98.5:1.5 er

Intensity [µV]

500000

0

10,400 1,50

6,0

7,0

8,0

9,0

10,0

11,0

Retention Time [min]

12,0

13,0

14,0

15,0

16,0

17,0

18,0

19,0

20,0

273

Chapter 3

Experimental Section

300000

O O S N

SLL-043 90.10 AD - CH14

9,067 49,95

10,853 50,05

O

Intensity [µV]

200000

(±)-141c

100000

0

Retention Time [min]

4,0

5,0

6,0

7,0

8,0

9,0

10,0

11,0

12,0

13,0

14,0

15,0

16,0

17,0

1500000

CM-III-120.1 90.10 AD - CH14

10,707 98,05

O O S N

1000000

O

Intensity [µV]

(+)-141c 98:2 er 500000

0

8,800 1,95

4,0

274

5,0

6,0

7,0

8,0

9,0

Retention Time [min]

10,0

11,0

12,0

13,0

14,0

15,0

16,0

17,0

Chapter 3

Experimental Section

SLL-040 90.10 AD - CH14

16,120 49,81

300000

O O S N

Intensity [µV]

200000

O Ph (±)-141d 30,187 50,19

100000

0

Retention Time [min]

5,0

10,0

15,0

20,0

25,0

30,0

35,0

40,0

45,0

2000000

CM-III-049 90.10 AD - CH14

29,653 98,57

O O S N

O Ph (-)-141d 98.5:1.5 er

Intensity [µV]

1000000

0 16,240 1,43

5,0

10,0

15,0

Retention Time [min]

20,0

25,0

30,0

35,0

40,0

45,0

275

Chapter 3

Experimental Section

O O S N

O (±)-142a

RID1 A, Refractive Index Signal (INSTAL\TEST1645.D) nRIU

O O S N

20000

41

15000

A25.995 re a: 91 79

O

10000

(+)-142a 93:7 er

A24.194 re a: 70 30

9. 6

5000

0

-5000

-10000

-15000

22

276

24

26

28

30

32

min

Chapter 3

Experimental Section

75 79 5

O O S N

Ar

ea

nRIU

:1

25.291

RID1 A, Refractive Index Signal (INSTAL\TEST1652.D)

4000

O (+)-142a 95:5 er (after crystallization)

3500

3000

2500

A23.680 re a: 10 58

4.

5

2000

1500

1000 21

22

23

24

25

26

27

min

O O S N

O (±)-142b

277

Chapter 3

Experimental Section

Ar 18.685 ea :8 68 30 7

RID1 A, Refractive Index Signal (INSTAL\TEST1646.D) nRIU

O O S N

17500

15000

O (-)-142b 94:6 er

12500

10000

A16.808 re a: 13 29 40

7500

5000

2500

0

-2500 5

10

15

O O S N

O (±)-142c

278

20

min

Chapter 3

Experimental Section

15000

94

Ar

ea

O O S N

50 6

20000

:8

16.150

RID1 A, Refractive Index Signal (INSTAL\TEST1644.D) nRIU

2. 7

10000

A14.840 re a: 41 86

O 5000

(+)-142c 95:5 er

0

-5000

-10000

-15000

10

12

14

16

18

24 22 20

200000

SLL-045 90.10 OD-H - CH14

O O S N

43,227 49,97 50,973 50,03

O Ph (±)-142d

Intensity [µV]

100000

0

Retention Time [min]

30,0

35,0

40,0

45,0

50,0

55,0

60,0

65,0

279

Chapter 3

Experimental Section

CM-III-121 90.10 OD-H - CH14

44,467 89,26

O O S N

Intensity [µV]

1000000

O Ph (-)-142d 89:11 er

500000

0

49,267 10,74 Retention Time [min]

30,0

35,0

40,0

45,0

50,0

55,0

60,0

CM-III-121 90.10 OD-H - CH14

44,467 99,43

O O S N

1000000

Intensity [µV]

O Ph (-)-142d 99.4:0.6 dr 500000

0

36,253 0,57

25,0

280

30,0

35,0

Retention Time [min]

40,0

45,0

50,0

55,0

60,0